Emerging Multi-omic Approaches to the Molecular Diagnosis of Mitochondrial Disease and Available Strategies for Treatment and Prevention

Alshial, E.E.; Abdulghaney, M.I.; Wadan, A.H.S.; Abdellatif, M.A.; Ramadan, N.E.; Suleiman, A.M.; Waheed, N.; Abdellatif, M.; Mohammed, H.S. Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview. Life Sci., 2023, 334, 122257.
[http://dx.doi.org/10.1016/j.lfs.2023.122257] [PMID: 37949207]

San-Millán, I. The key role of mitochondrial function in health and disease. Antioxidants, 2023, 12(4), 782.
[http://dx.doi.org/10.3390/antiox12040782] [PMID: 37107158]

Chinnery, P.F. Primary mitochondrial disorders overview; GeneReviews, 2021.

Aldossary, A.M.; Tawfik, E.A.; Alomary, M.N.; Alsudir, S.A.; Alfahad, A.J.; Alshehri, A.A.; Almughem, F.A.; Mohammed, R.Y.; Alzaydi, M.M. Recent advances in mitochondrial diseases: From molecular insights to therapeutic perspectives. Saudi Pharm. J., 2022, 30(8), 1065-1078.
[http://dx.doi.org/10.1016/j.jsps.2022.05.011] [PMID: 36164575]

Stenton, S.L.; Prokisch, H. Advancing genomic approaches to the molecular diagnosis of mitochondrial disease. Essays Biochem., 2018, 62(3), 399-408.
[http://dx.doi.org/10.1042/EBC20170110] [PMID: 29950319]

Grady, J.P.; Pickett, S.J.; Ng, Y.S.; Alston, C.L.; Blakely, E.L.; Hardy, S.A.; Feeney, C.L.; Bright, A.A.; Schaefer, A.M.; Gorman, G.S.; McNally, R.J.Q.; Taylor, R.W.; Turnbull, D.M.; McFarland, R. mt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol. Med., 2018, 10(6), e8262.
[http://dx.doi.org/10.15252/emmm.201708262] [PMID: 29735722]

Korchivaia, E.; Silaeva, Y.; Mazunin, I.; Volodyaev, I. The mitochondrial challenge: Disorders and prevention strategies. Biosystems, 2023, 223, 104819.
[http://dx.doi.org/10.1016/j.biosystems.2022.104819] [PMID: 36450320]

El-Hattab, A.W.; Scaglia, F. Mitochondrial cytopathies. Cell Calcium, 2016, 60(3), 199-206.
[http://dx.doi.org/10.1016/j.ceca.2016.03.003] [PMID: 26996063]

Lake, N.J.; Bird, M.J.; Isohanni, P.; Paetau, A. Leigh syndrome. J. Neuropathol. Exp. Neurol., 2015, 74(6), 482-492.
[http://dx.doi.org/10.1097/NEN.0000000000000195] [PMID: 25978847]

Schubert Baldo, M.; Vilarinho, L. Molecular basis of Leigh syndrome: A current look. Orphanet J. Rare Dis., 2020, 15(1), 31.
[http://dx.doi.org/10.1186/s13023-020-1297-9] [PMID: 31996241]

Avula, S.; Parikh, S.; Demarest, S.; Kurz, J.; Gropman, A. Treatment of mitochondrial disorders. Curr. Treat. Options Neurol., 2014, 16(6), 292.
[http://dx.doi.org/10.1007/s11940-014-0292-7] [PMID: 24700433]

Quinzii, C.M.; Emmanuele, V.; Hirano, M. Clinical presentations of coenzyme q10 deficiency syndrome. Mol. Syndromol., 2014, 5(3-4), 141-146.
[http://dx.doi.org/10.1159/000360490] [PMID: 25126046]

Pfeffer, G.; Horvath, R.; Klopstock, T.; Mootha, V.K.; Suomalainen, A.; Koene, S.; Hirano, M.; Zeviani, M.; Bindoff, L.A.; Yu-Wai-Man, P.; Hanna, M.; Carelli, V.; McFarland, R.; Majamaa, K.; Turnbull, D.M.; Smeitink, J.; Chinnery, P.F. New treatments for mitochondrial disease—no time to drop our standards. Nat. Rev. Neurol., 2013, 9(8), 474-481.
[http://dx.doi.org/10.1038/nrneurol.2013.129] [PMID: 23817350]

Gorman, G.S.; Chinnery, P.F.; DiMauro, S.; Hirano, M.; Koga, Y.; McFarland, R.; Suomalainen, A.; Thorburn, D.R.; Zeviani, M.; Turnbull, D.M. Mitochondrial diseases. Nat. Rev. Dis. Primers, 2016, 2(1), 16080.
[http://dx.doi.org/10.1038/nrdp.2016.80] [PMID: 27775730]

McCormick, E.; Place, E.; Falk, M.J. Molecular genetic testing for mitochondrial disease: From one generation to the next. Neurotherapeutics, 2013, 10(2), 251-261.
[http://dx.doi.org/10.1007/s13311-012-0174-1] [PMID: 23269497]

McCormick, E.M.; Zolkipli-Cunningham, Z.; Falk, M.J. Mitochondrial disease genetics update: Recent insights into the molecular diagnosis and expanding phenotype of primary mitochondrial disease. Curr. Opin. Pediatr., 2018, 30(6), 714-724.
[http://dx.doi.org/10.1097/MOP.0000000000000686] [PMID: 30199403]

Thompson, K.; Collier, J.J.; Glasgow, R.I.C.; Robertson, F.M.; Pyle, A.; Blakely, E.L.; Alston, C.L.; Oláhová, M.; McFarland, R.; Taylor, R.W. Recent advances in understanding the molecular genetic basis of mitochondrial disease. J. Inherit. Metab. Dis., 2020, 43(1), 36-50.
[http://dx.doi.org/10.1002/jimd.12104] [PMID: 31021000]

Serre, V.; Rozanska, A.; Beinat, M.; Chretien, D.; Boddaert, N.; Munnich, A.; Rötig, A.; Chrzanowska-Lightowlers, Z.M. Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency. Biochim. Biophys. Acta Mol. Basis Dis., 2013, 1832(8), 1304-1312.
[http://dx.doi.org/10.1016/j.bbadis.2013.04.014] [PMID: 23603806]

Meienberg, J.; Bruggmann, R.; Oexle, K.; Matyas, G. Clinical sequencing: Is WGS the better WES? Hum. Genet., 2016, 135(3), 359-362.
[http://dx.doi.org/10.1007/s00439-015-1631-9] [PMID: 26742503]

Valenti, D.; Vacca, R. Primary and secondary mitochondrial diseases: Etiologies and therapeutic strategies. J. Clin. Med., 2022, 11(14), 4209.
[http://dx.doi.org/10.3390/jcm11144209] [PMID: 35887983]

Tinker, R.J.; Lim, A.Z.; Stefanetti, R.J.; McFarland, R. Current and emerging clinical treatment in mitochondrial disease. Mol. Diagn. Ther., 2021, 25(2), 181-206.
[http://dx.doi.org/10.1007/s40291-020-00510-6] [PMID: 33646563]

Braun, E. Mitochondrial replacement techniques for treating infertility. J. Med. Ethics, 2024, jme-2023-109660.
[http://dx.doi.org/10.1136/jme-2023-109660] [PMID: 38383152]

Watson, E.; Davis, R.; Sue, C.M. New diagnostic pathways for mitochondrial disease. J. Transl. Genet. Genom., 2020, 4, 188-202.

Lightowlers, R.N.; Taylor, R.W.; Turnbull, D.M. Mutations causing mitochondrial disease: What is new and what challenges remain? Science, 2015, 349(6255), 1494-1499.
[http://dx.doi.org/10.1126/science.aac7516] [PMID: 26404827]

Ng, Y.S.; Turnbull, D.M. Mitochondrial disease: Genetics and management. J. Neurol., 2016, 263(1), 179-191.
[http://dx.doi.org/10.1007/s00415-015-7884-3] [PMID: 26315846]

Legati, A.; Reyes, A.; Nasca, A.; Invernizzi, F.; Lamantea, E.; Tiranti, V.; Garavaglia, B.; Lamperti, C.; Ardissone, A.; Moroni, I.; Robinson, A.; Ghezzi, D.; Zeviani, M. New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochim. Biophys. Acta Bioenerg., 2016, 1857(8), 1326-1335.
[http://dx.doi.org/10.1016/j.bbabio.2016.02.022] [PMID: 26968897]

Stenton, S.L.; Prokisch, H. Genetics of mitochondrial diseases: Identifying mutations to help diagnosis. EBioMedicine, 2020, 56, 102784.
[http://dx.doi.org/10.1016/j.ebiom.2020.102784] [PMID: 32454403]

Wu, T.H.; Peng, J.; Yang, L.; Chen, Y.H.; Lu, X.L.; Huang, J.T.; You, J.Y.; Ou-Yang, W.X.; Sun, Y.Y.; Xue, Y.N.; Mao, X.; Yan, H.M.; Ren, R.N.; Xie, J.; Chen, Z.H.; Zhang, V.W.; Lyu, G.Z.; He, F. Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: A retrospective analysis. Sci. Rep., 2023, 13(1), 4193.
[http://dx.doi.org/10.1038/s41598-023-31134-5] [PMID: 36918699]

Ahmad, R.; Hasan, M.Y. Next-generation sequencing technology in the diagnosis of mitochondrial disorders. Int. J. Health Sci., 2021, 15(1), 1-2.
[PMID: 33456435]

Stendel, C.; Neuhofer, C.; Floride, E.; Yuqing, S.; Ganetzky, R.D.; Park, J.; Freisinger, P.; Kornblum, C.; Kleinle, S.; Schöls, L.; Distelmaier, F.; Stettner, G.M.; Büchner, B.; Falk, M.J.; Mayr, J.A.; Synofzik, M.; Abicht, A.; Haack, T.B.; Prokisch, H.; Wortmann, S.B.; Murayama, K.; Fang, F.; Klopstock, T. Delineating MT-ATP6 -associated disease. Neurol. Genet., 2020, 6(1), e393.
[http://dx.doi.org/10.1212/NXG.0000000000000393] [PMID: 32042921]

Herbers, E.; Kekäläinen, N.J.; Hangas, A.; Pohjoismäki, J.L.; Goffart, S. Tissue specific differences in mitochondrial DNA maintenance and expression. Mitochondrion, 2019, 44, 85-92.
[http://dx.doi.org/10.1016/j.mito.2018.01.004] [PMID: 29339192]

Belkadi, A.; Bolze, A.; Itan, Y.; Cobat, A.; Vincent, Q.B.; Antipenko, A.; Shang, L.; Boisson, B.; Casanova, J.L.; Abel, L. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc. Natl. Acad. Sci. USA, 2015, 112(17), 5473-5478.
[http://dx.doi.org/10.1073/pnas.1418631112] [PMID: 25827230]

Frazier, A. E.; Compton, A. G.; Kishita, Y.; Hock, D. H.; Welch, A. E.; Amarasekera, S. S.; Rius, R.; Formosa, L. E.; Imai-Okazaki, A.; Francis, D. Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus. Med, 2021, 2, 49-73.

Alston, C.L.; Stenton, S.L.; Hudson, G.; Prokisch, H.; Taylor, R.W. The genetics of mitochondrial disease: Dissecting mitochondrial pathology using multi-omic pipelines. J. Pathol., 2021, 254(4), 430-442.
[http://dx.doi.org/10.1002/path.5641] [PMID: 33586140]

Bourchany, A.; Thauvin-Robinet, C.; Lehalle, D.; Bruel, A.L.; Masurel-Paulet, A.; Jean, N.; Nambot, S.; Willems, M.; Lambert, L.; El Chehadeh-Djebbar, S.; Schaefer, E.; Jaquette, A.; St-Onge, J.; Poe, C.; Jouan, T.; Chevarin, M.; Callier, P.; Mosca-Boidron, A.L.; Laurent, N.; Lefebvre, M.; Huet, F.; Houcinat, N.; Moutton, S.; Philippe, C.; Tran-Mau-Them, F.; Vitobello, A.; Kuentz, P.; Duffourd, Y.; Rivière, J.B.; Thevenon, J.; Faivre, L. Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses. Eur. J. Med. Genet., 2017, 60(11), 595-604.
[http://dx.doi.org/10.1016/j.ejmg.2017.08.011] [PMID: 28807864]

Schon, K.R.; Ratnaike, T.; van den Ameele, J.; Horvath, R.; Chinnery, P.F. Mitochondrial diseases: A diagnostic revolution. Trends Genet., 2020, 36(9), 702-717.
[http://dx.doi.org/10.1016/j.tig.2020.06.009] [PMID: 32674947]

Simon, M.T.; Eftekharian, S.S.; Stover, A.E.; Osborne, A.F.; Braffman, B.H.; Chang, R.C.; Wang, R.Y.; Steenari, M.R.; Tang, S.; Hwu, P.W.L.; Taft, R.J.; Benke, P.J.; Abdenur, J.E. Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes. Mol. Genet. Metab., 2019, 126(1), 53-63.
[http://dx.doi.org/10.1016/j.ymgme.2018.11.001] [PMID: 30473481]

Alston, C.L.; Veling, M.T.; Heidler, J.; Taylor, L.S.; Alaimo, J.T.; Sung, A.Y.; He, L.; Hopton, S.; Broomfield, A.; Pavaine, J.; Diaz, J.; Leon, E.; Wolf, P.; McFarland, R.; Prokisch, H.; Wortmann, S.B.; Bonnen, P.E.; Wittig, I.; Pagliarini, D.J.; Taylor, R.W. Pathogenic bi-allelic mutations in NDUFAF8 cause Leigh syndrome with an isolated complex I deficiency. Am. J. Hum. Genet., 2020, 106(1), 92-101.
[http://dx.doi.org/10.1016/j.ajhg.2019.12.001] [PMID: 31866046]

Macken, W.L.; Falabella, M.; Pizzamiglio, C.; Woodward, C.E.; Scotchman, E.; Chitty, L.S.; Polke, J.M.; Bugiardini, E.; Hanna, M.G.; Vandrovcova, J.; Chandler, N.; Labrum, R.; Pitceathly, R.D.S. Enhanced mitochondrial genome analysis: Bioinformatic and long-read sequencing advances and their diagnostic implications. Expert Rev. Mol. Diagn., 2023, 23(9), 797-814.
[http://dx.doi.org/10.1080/14737159.2023.2241365] [PMID: 37642407]

Mu, W.; Li, B.; Wu, S.; Chen, J.; Sain, D.; Xu, D.; Black, M.H.; Karam, R.; Gillespie, K.; Farwell Hagman, K.D.; Guidugli, L.; Pronold, M.; Elliott, A.; Lu, H.M. Detection of structural variation using target captured next-generation sequencing data for genetic diagnostic testing. Genet. Med., 2019, 21(7), 1603-1610.
[http://dx.doi.org/10.1038/s41436-018-0397-6] [PMID: 30563988]

Gusic, M.; Prokisch, H. Genetic basis of mitochondrial diseases. FEBS Lett., 2021, 595(8), 1132-1158.
[http://dx.doi.org/10.1002/1873-3468.14068] [PMID: 33655490]

Mizuguchi, T.; Suzuki, T.; Abe, C.; Umemura, A.; Tokunaga, K.; Kawai, Y.; Nakamura, M.; Nagasaki, M.; Kinoshita, K.; Okamura, Y.; Miyatake, S.; Miyake, N.; Matsumoto, N. A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing. J. Hum. Genet., 2019, 64(5), 359-368.
[http://dx.doi.org/10.1038/s10038-019-0569-5] [PMID: 30760880]

Clark, M.M.; Hildreth, A.; Batalov, S.; Ding, Y.; Chowdhury, S.; Watkins, K.; Ellsworth, K.; Camp, B.; Kint, C.I.; Yacoubian, C.; Farnaes, L.; Bainbridge, M.N.; Beebe, C.; Braun, J.J.A.; Bray, M.; Carroll, J.; Cakici, J.A.; Caylor, S.A.; Clarke, C.; Creed, M.P.; Friedman, J.; Frith, A.; Gain, R.; Gaughran, M.; George, S.; Gilmer, S.; Gleeson, J.; Gore, J.; Grunenwald, H.; Hovey, R.L.; Janes, M.L.; Lin, K.; McDonagh, P.D.; McBride, K.; Mulrooney, P.; Nahas, S.; Oh, D.; Oriol, A.; Puckett, L.; Rady, Z.; Reese, M.G.; Ryu, J.; Salz, L.; Sanford, E.; Stewart, L.; Sweeney, N.; Tokita, M.; Van Der Kraan, L.; White, S.; Wigby, K.; Williams, B.; Wong, T.; Wright, M.S.; Yamada, C.; Schols, P.; Reynders, J.; Hall, K.; Dimmock, D.; Veeraraghavan, N.; Defay, T.; Kingsmore, S.F. Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. Sci. Transl. Med., 2019, 11(489), eaat6177.
[http://dx.doi.org/10.1126/scitranslmed.aat6177] [PMID: 31019026]

Ferri, L.; Dionisi-Vici, C.; Taurisano, R.; Vaz, F.M.; Guerrini, R.; Morrone, A. When silence is noise: Infantile-onset Barth syndrome caused by a synonymous substitution affectingTAZ gene transcription. Clin. Genet., 2016, 90(5), 461-465.
[http://dx.doi.org/10.1111/cge.12756] [PMID: 26853223]

Mertes, C.; Scheller, I.; Yépez, V.A.; Çelik, M.H.; Liang, Y.; Kremer, L.S.; Gusic, M.; Prokisch, H.; Gagneur, J. Detection of aberrant splicing events in RNA-seq data with FRASER. bioRxiv, 2019.
[http://dx.doi.org/10.1101/2019.12.18.866830]

Kremer, L.S.; Bader, D.M.; Mertes, C.; Kopajtich, R.; Pichler, G.; Iuso, A.; Haack, T.B.; Graf, E.; Schwarzmayr, T.; Terrile, C.; Koňaříková, E.; Repp, B.; Kastenmüller, G.; Adamski, J.; Lichtner, P.; Leonhardt, C.; Funalot, B.; Donati, A.; Tiranti, V.; Lombes, A.; Jardel, C.; Gläser, D.; Taylor, R.W.; Ghezzi, D.; Mayr, J.A.; Rötig, A.; Freisinger, P.; Distelmaier, F.; Strom, T.M.; Meitinger, T.; Gagneur, J.; Prokisch, H. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat. Commun., 2017, 8(1), 15824.
[http://dx.doi.org/10.1038/ncomms15824] [PMID: 28604674]

Li, M.; Zhao, L.; Page-McCaw, P.S.; Chen, W. Zebrafish genome engineering using the CRISPR–Cas9 system. Trends Genet., 2016, 32(12), 815-827.
[http://dx.doi.org/10.1016/j.tig.2016.10.005] [PMID: 27836208]

Cummings, B.B.; Marshall, J.L.; Tukiainen, T.; Lek, M.; Donkervoort, S.; Foley, A.R.; Bolduc, V.; Waddell, L.B.; Sandaradura, S.A.; O’Grady, G.L.; Estrella, E.; Reddy, H.M.; Zhao, F.; Weisburd, B.; Karczewski, K.J.; O’Donnell-Luria, A.H.; Birnbaum, D.; Sarkozy, A.; Hu, Y.; Gonorazky, H.; Claeys, K.; Joshi, H.; Bournazos, A.; Oates, E.C.; Ghaoui, R.; Davis, M.R.; Laing, N.G.; Topf, A.; Kang, P.B.; Beggs, A.H.; North, K.N.; Straub, V.; Dowling, J.J.; Muntoni, F.; Clarke, N.F.; Cooper, S.T.; Bönnemann, C.G.; MacArthur, D.G. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci. Transl. Med., 2017, 9(386), eaal5209.
[http://dx.doi.org/10.1126/scitranslmed.aal5209] [PMID: 28424332]

Wilmer, M.J.; Kluijtmans, L.A.J.; van der Velden, T.J.; Willems, P.H.; Scheffer, P.G.; Masereeuw, R.; Monnens, L.A.; van den Heuvel, L.P.; Levtchenko, E.N. Cysteamine restores glutathione redox status in cultured cystinotic proximal tubular epithelial cells. Biochim. Biophys. Acta Mol. Basis Dis., 2011, 1812(6), 643-651.
[http://dx.doi.org/10.1016/j.bbadis.2011.02.010] [PMID: 21371554]

Ferraro, N.M.; Strober, B.J.; Einson, J.; Abell, N.S.; Aguet, F.; Barbeira, A.N.; Brandt, M.; Bucan, M.; Castel, S.E.; Davis, J.R.; Greenwald, E.; Hess, G.T.; Hilliard, A.T.; Kember, R.L.; Kotis, B.; Park, Y.; Peloso, G.; Ramdas, S.; Scott, A.J.; Smail, C.; Tsang, E.K.; Zekavat, S.M.; Ziosi, M.; Aradhana; Ardlie, K.G.; Assimes, T.L.; Bassik, M.C.; Brown, C.D.; Correa, A.; Hall, I.; Im, H.K.; Li, X.; Natarajan, P.; Lappalainen, T.; Mohammadi, P.; Montgomery, S.B.; Battle, A.; Aguet, F.; Anand, S.; Ardlie, K.G.; Gabriel, S.; Getz, G.A.; Graubert, A.; Hadley, K.; Handsaker, R.E.; Huang, K.H.; Kashin, S.; Li, X.; MacArthur, D.G.; Meier, S.R.; Nedzel, J.L.; Nguyen, D.T.; Segrè, A.V.; Todres, E.; Balliu, B.; Barbeira, A.N.; Battle, A.; Bonazzola, R.; Brown, A.; Brown, C.D.; Castel, S.E.; Conrad, D.F.; Cotter, D.J.; Cox, N.; Das, S.; de Goede, O.M.; Dermitzakis, E.T.; Einson, J.; Engelhardt, B.E.; Eskin, E.; Eulalio, T.Y.; Ferraro, N.M.; Flynn, E.D.; Fresard, L.; Gamazon, E.R.; Garrido-Martín, D.; Gay, N.R.; Gloudemans, M.J.; Guigó, R.; Hame, A.R.; He, Y.; Hoffman, P.J.; Hormozdiari, F.; Hou, L.; Im, H.K.; Jo, B.; Kasela, S.; Kellis, M.; Kim-Hellmuth, S.; Kwong, A.; Lappalainen, T.; Li, X.; Liang, Y.; Mangul, S.; Mohammadi, P.; Montgomery, S.B.; Muñoz-Aguirre, M.; Nachun, D.C.; Nobel, A.B.; Oliva, M.; Park, Y.S.; Park, Y.; Parsana, P.; Rao, A.S.; Reverter, F.; Rouhana, J.M.; Sabatti, C.; Saha, A.; Stephens, M.; Stranger, B.E.; Strober, B.J.; Teran, N.A.; Viñuela, A.; Wang, G.; Wen, X.; Wright, F.; Wucher, V.; Zou, Y.; Ferreira, P.G.; Li, G.; Melé, M.; Yeger-Lotem, E.; Barcus, M.E.; Bradbury, D.; Krubit, T.; McLean, J.A.; Qi, L.; Robinson, K.; Roche, N.V.; Smith, A.M.; Sobin, L.; Tabor, D.E.; Undale, A.; Bridge, J.; Brigham, L.E.; Foster, B.A.; Gillard, B.M.; Hasz, R.; Hunter, M.; Johns, C.; Johnson, M.; Karasik, E.; Kopen, G.; Leinweber, W.F.; McDonald, A.; Moser, M.T.; Myer, K.; Ramsey, K.D.; Roe, B.; Shad, S.; Thomas, J.A.; Walters, G.; Washington, M.; Wheeler, J.; Jewell, S.D.; Rohrer, D.C.; Valley, D.R.; Davis, D.A.; Mash, D.C.; Branton, P.A.; Barker, L.K.; Gardiner, H.M.; Mosavel, M.; Siminoff, L.A.; Flicek, P.; Haeussler, M.; Juettemann, T.; Kent, W.J.; Lee, C.M.; Powell, C.C.; Rosenbloom, K.R.; Ruffier, M.; Sheppard, D.; Taylor, K.; Trevanion, S.J.; Zerbino, D.R.; Abell, N.S.; Akey, J.; Chen, L.; Demanelis, K.; Doherty, J.A.; Feinberg, A.P.; Hansen, K.D.; Hickey, P.F.; Jasmine, F.; Jiang, L.; Kaul, R.; Kibriya, M.G.; Li, J.B.; Li, Q.; Lin, S.; Linder, S.E.; Pierce, B.L.; Rizzardi, L.F.; Skol, A.D.; Smith, K.S.; Snyder, M.; Stamatoyannopoulos, J.; Tang, H.; Wang, M.; Carithers, L.J.; Guan, P.; Koester, S.E.; Little, A.R.; Moore, H.M.; Nierras, C.R.; Rao, A.K.; Vaught, J.B.; Volpi, S. Transcriptomic signatures across human tissues identify functional rare genetic variation. Science, 2020, 369(6509), eaaz5900.
[http://dx.doi.org/10.1126/science.aaz5900] [PMID: 32913073]

Aguet, F.; Anand, S.; Ardlie, K.G.; Gabriel, S.; Getz, G.A.; Graubert, A.; Hadley, K.; Handsaker, R.E.; Huang, K.H.; Kashin, S.; Li, X.; MacArthur, D.G.; Meier, S.R.; Nedzel, J.L.; Nguyen, D.T.; Segrè, A.V.; Todres, E.; Balliu, B.; Barbeira, A.N.; Battle, A.; Bonazzola, R.; Brown, A.; Brown, C.D.; Castel, S.E.; Conrad, D.F.; Cotter, D.J.; Cox, N.; Das, S.; de Goede, O.M.; Dermitzakis, E.T.; Einson, J.; Engelhardt, B.E.; Eskin, E.; Eulalio, T.Y.; Ferraro, N.M.; Flynn, E.D.; Fresard, L.; Gamazon, E.R.; Garrido-Martín, D.; Gay, N.R.; Gloudemans, M.J.; Guigó, R.; Hame, A.R.; He, Y.; Hoffman, P.J.; Hormozdiari, F.; Hou, L.; Im, H.K.; Jo, B.; Kasela, S.; Kellis, M.; Kim-Hellmuth, S.; Kwong, A.; Lappalainen, T.; Li, X.; Liang, Y.; Mangul, S.; Mohammadi, P.; Montgomery, S.B.; Muñoz-Aguirre, M.; Nachun, D.C.; Nobel, A.B.; Oliva, M.; Park, Y.S.; Park, Y.; Parsana, P.; Rao, A.S.; Reverter, F.; Rouhana, J.M.; Sabatti, C.; Saha, A.; Stephens, M.; Stranger, B.E.; Strober, B.J.; Teran, N.A.; Viñuela, A.; Wang, G.; Wen, X.; Wright, F.; Wucher, V.; Zou, Y.; Ferreira, P.G.; Li, G.; Melé, M.; Yeger-Lotem, E.; Barcus, M.E.; Bradbury, D.; Krubit, T.; McLean, J.A.; Qi, L.; Robinson, K.; Roche, N.V.; Smith, A.M.; Sobin, L.; Tabor, D.E.; Undale, A.; Bridge, J.; Brigham, L.E.; Foster, B.A.; Gillard, B.M.; Hasz, R.; Hunter, M.; Johns, C.; Johnson, M.; Karasik, E.; Kopen, G.; Leinweber, W.F.; McDonald, A.; Moser, M.T.; Myer, K.; Ramsey, K.D.; Roe, B.; Shad, S.; Thomas, J.A.; Walters, G.; Washington, M.; Wheeler, J.; Jewell, S.D.; Rohrer, D.C.; Valley, D.R.; Davis, D.A.; Mash, D.C.; Branton, P.A.; Barker, L.K.; Gardiner, H.M.; Mosavel, M.; Siminoff, L.A.; Flicek, P.; Haeussler, M.; Juettemann, T.; Kent, W.J.; Lee, C.M.; Powell, C.C.; Rosenbloom, K.R.; Ruffier, M.; Sheppard, D.; Taylor, K.; Trevanion, S.J.; Zerbino, D.R.; Abell, N.S.; Akey, J.; Chen, L.; Demanelis, K.; Doherty, J.A.; Feinberg, A.P.; Hansen, K.D.; Hickey, P.F.; Jasmine, F.; Jiang, L.; Kaul, R.; Kibriya, M.G.; Li, J.B.; Li, Q.; Lin, S.; Linder, S.E.; Pierce, B.L.; Rizzardi, L.F.; Skol, A.D.; Smith, K.S.; Snyder, M.; Stamatoyannopoulos, J.; Tang, H.; Wang, M.; Carithers, L.J.; Guan, P.; Koester, S.E.; Little, A.R.; Moore, H.M.; Nierras, C.R.; Rao, A.K.; Vaught, J.B.; Volpi, S. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science, 2020, 369(6509), 1318-1330.
[http://dx.doi.org/10.1126/science.aaz1776] [PMID: 32913098]

Papatheodorou, I.; Moreno, P.; Manning, J.; Fuentes, A.M.; George, N.; Fexova, S.; Fonseca, N.A.; Füllgrabe, A.; Green, M.; Huang, N.; Huerta, L.; Iqbal, H.; Jianu, M.; Mohammed, S.; Zhao, L.; Jarnuczak, A.F.; Jupp, S.; Marioni, J.; Meyer, K.; Petryszak, R.; Prada Medina, C.A.; Talavera-López, C.; Teichmann, S.; Vizcaino, J.A.; Brazma, A. Expression Atlas update: From tissues to single cells. Nucleic Acids Res., 2020, 48(D1), D77-D83.
[PMID: 31665515]

Gonorazky, H.D.; Naumenko, S.; Ramani, A.K.; Nelakuditi, V.; Mashouri, P.; Wang, P.; Kao, D.; Ohri, K.; Viththiyapaskaran, S.; Tarnopolsky, M.A.; Mathews, K.D.; Moore, S.A.; Osorio, A.N.; Villanova, D.; Kemaladewi, D.U.; Cohn, R.D.; Brudno, M.; Dowling, J.J. Expanding the boundaries of RNA sequencing as a diagnostic tool for rare mendelian disease. Am. J. Hum. Genet., 2019, 104(3), 466-483.
[http://dx.doi.org/10.1016/j.ajhg.2019.01.012] [PMID: 30827497]

Aicher, J.K.; Jewell, P.; Vaquero-Garcia, J.; Barash, Y.; Bhoj, E.J. Mapping RNA splicing variations in clinically accessible and nonaccessible tissues to facilitate Mendelian disease diagnosis using RNA-seq. Genet. Med., 2020, 22(7), 1181-1190.
[http://dx.doi.org/10.1038/s41436-020-0780-y] [PMID: 32225167]

Mertes, C.; Scheller, I. F. Detection of aberrant splicing events in RNA-seq data using FRASER. Nat Commun., 2021, 12, 529.

Graves, P.R.; Haystead, T.A.J. Molecular biologist’s guide to proteomics. Microbiol. Mol. Biol. Rev., 2002, 66(1), 39-63.
[http://dx.doi.org/10.1128/MMBR.66.1.39-63.2002] [PMID: 11875127]

McArdle, A.J.; Menikou, S. What is proteomics? Arch Dis Child Educ Pract Ed. , 2021, 106(3), 178-181.

Stenton, S.L.; Kremer, L.S.; Kopajtich, R.; Ludwig, C.; Prokisch, H. The diagnosis of inborn errors of metabolism by an integrative “multi-omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics. J. Inherit. Metab. Dis., 2020, 43(1), 25-35.
[http://dx.doi.org/10.1002/jimd.12130] [PMID: 31119744]

Sahni, N.; Yi, S.; Taipale, M.; Fuxman Bass, J.I.; Coulombe-Huntington, J.; Yang, F.; Peng, J.; Weile, J.; Karras, G.I.; Wang, Y.; Kovács, I.A.; Kamburov, A.; Krykbaeva, I.; Lam, M.H.; Tucker, G.; Khurana, V.; Sharma, A.; Liu, Y.Y.; Yachie, N.; Zhong, Q.; Shen, Y.; Palagi, A.; San-Miguel, A.; Fan, C.; Balcha, D.; Dricot, A.; Jordan, D.M.; Walsh, J.M.; Shah, A.A.; Yang, X.; Stoyanova, A.K.; Leighton, A.; Calderwood, M.A.; Jacob, Y.; Cusick, M.E.; Salehi-Ashtiani, K.; Whitesell, L.J.; Sunyaev, S.; Berger, B.; Barabási, A.L.; Charloteaux, B.; Hill, D.E.; Hao, T.; Roth, F.P.; Xia, Y.; Walhout, A.J.M.; Lindquist, S.; Vidal, M. Widespread macromolecular interaction perturbations in human genetic disorders. Cell, 2015, 161(3), 647-660.
[http://dx.doi.org/10.1016/j.cell.2015.04.013] [PMID: 25910212]

Lake, N.J.; Webb, B.D.; Stroud, D.A.; Richman, T.R.; Ruzzenente, B.; Compton, A.G.; Mountford, H.S.; Pulman, J.; Zangarelli, C.; Rio, M.; Boddaert, N.; Assouline, Z.; Sherpa, M.D.; Schadt, E.E.; Houten, S.M.; Byrnes, J.; McCormick, E.M.; Zolkipli-Cunningham, Z.; Haude, K.; Zhang, Z.; Retterer, K.; Bai, R.; Calvo, S.E.; Mootha, V.K.; Christodoulou, J.; Rötig, A.; Filipovska, A.; Cristian, I.; Falk, M.J.; Metodiev, M.D.; Thorburn, D.R. Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and leigh syndrome. Am. J. Hum. Genet., 2017, 101(2), 239-254.
[http://dx.doi.org/10.1016/j.ajhg.2017.07.005] [PMID: 28777931]

Borna, N. N.; Kishita, Y.; Kohda, M.; Lim, S. C.; Shimura, M.; Wu, Y.; Mogushi, K.; Yatsuka, Y.; Harashima, H.; Hisatomi, Y. Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome. Neurogenetics, 2019, 20, 9-25.

Filipovska, A.; Rackham, O. Pentatricopeptide repeats. RNA Biol., 2013, 10(9), 1426-1432.
[http://dx.doi.org/10.4161/rna.24769] [PMID: 23635770]

Guarani, V.; Paulo, J.; Zhai, B.; Huttlin, E.L.; Gygi, S.P.; Harper, J.W. TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex. Mol. Cell. Biol., 2014, 34(5), 847-861.
[http://dx.doi.org/10.1128/MCB.01551-13] [PMID: 24344204]

Boenzi, S.; Diodato, D. Biomarkers for mitochondrial energy metabolism diseases. Essays Biochem., 2018, 62(3), 443-454.
[http://dx.doi.org/10.1042/EBC20170111] [PMID: 29980631]

Smuts, I.; van der Westhuizen, F.H.; Louw, R.; Mienie, L.J.; Engelke, U.F.H.; Wevers, R.A.; Mason, S.; Koekemoer, G.; Reinecke, C.J. Disclosure of a putative biosignature for respiratory chain disorders through a metabolomics approach. Metabolomics, 2013, 9(2), 379-391.
[http://dx.doi.org/10.1007/s11306-012-0455-z]

Thomas, R.H.; Hunter, A.; Butterworth, L.; Feeney, C.; Graves, T.D.; Holmes, S.; Hossain, P.; Lowndes, J.; Sharpe, J.; Upadhyaya, S.; Varhaug, K.N.; Votruba, M.; Wheeler, R.; Staley, K.; Rahman, S. Research priorities for mitochondrial disorders: Current landscape and patient and professional views. J. Inherit. Metab. Dis., 2022, 45(4), 796-803.
[http://dx.doi.org/10.1002/jimd.12521] [PMID: 35543492]

Sharma, R.; Reinstadler, B.; Engelstad, K.; Skinner, O.S.; Stackowitz, E.; Haller, R.G.; Clish, C.B.; Pierce, K.; Walker, M.A.; Fryer, R.; Oglesbee, D.; Mao, X.; Shungu, D.C.; Khatri, A.; Hirano, M.; De Vivo, D.C.; Mootha, V.K. Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity. J. Clin. Invest., 2021, 131(2), e136055.
[http://dx.doi.org/10.1172/JCI136055] [PMID: 33463549]

Esterhuizen, K.; van der Westhuizen, F.H.; Louw, R. Metabolomics of mitochondrial disease. Mitochondrion, 2017, 35, 97-110.
[http://dx.doi.org/10.1016/j.mito.2017.05.012] [PMID: 28576558]

Coene, K.L.M.; Kluijtmans, L.A.J.; van der Heeft, E.; Engelke, U.F.H.; de Boer, S.; Hoegen, B.; Kwast, H.J.T.; van de Vorst, M.; Huigen, M.C.D.G.; Keularts, I.M.L.W.; Schreuder, M.F.; van Karnebeek, C.D.M.; Wortmann, S.B.; de Vries, M.C.; Janssen, M.C.H.; Gilissen, C.; Engel, J.; Wevers, R.A. Next-generation metabolic screening: Targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients. J. Inherit. Metab. Dis., 2018, 41(3), 337-353.
[http://dx.doi.org/10.1007/s10545-017-0131-6] [PMID: 29453510]

Landsverk, M.L.; Zhang, V.W.; Wong, L.J.C.; Andersson, H.C. A SUCLG1 mutation in a patient with mitochondrial DNA depletion and congenital anomalies. Mol. Genet. Metab. Rep., 2014, 1, 451-454.
[http://dx.doi.org/10.1016/j.ymgmr.2014.09.007] [PMID: 27896121]

Tort, F.; García-Silva, M.T.; Ferrer-Cortès, X.; Navarro-Sastre, A.; Garcia-Villoria, J.; Coll, M.J.; Vidal, E.; Jiménez-Almazán, J.; Dopazo, J.; Briones, P.; Elpeleg, O.; Ribes, A. Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. Mol. Genet. Metab., 2013, 110(1-2), 73-77.
[http://dx.doi.org/10.1016/j.ymgme.2013.04.021] [PMID: 23707711]

Shayota, B.J. Biomarkers of mitochondrial disorders. Neurotherapeutics, 2024, 21(1), e00325.
[http://dx.doi.org/10.1016/j.neurot.2024.e00325] [PMID: 38295557]

Knottnerus, S.J.G.; Pras-Raves, M.L.; van der Ham, M.; Ferdinandusse, S.; Houtkooper, R.H.; Schielen, P.C.J.I.; Visser, G.; Wijburg, F.A.; de Sain-van der Velden, M.G.M. Prediction of VLCAD deficiency phenotype by a metabolic fingerprint in newborn screening bloodspots. Biochim. Biophys. Acta Mol. Basis Dis., 2020, 1866(6), 165725.
[http://dx.doi.org/10.1016/j.bbadis.2020.165725] [PMID: 32061778]

Merritt, J.L., II; Norris, M.; Kanungo, S. Fatty acid oxidation disorders. Ann. Transl. Med., 2018, 6(24), 473.
[http://dx.doi.org/10.21037/atm.2018.10.57] [PMID: 30740404]

Maguolo, A.; Rodella, G.; Dianin, A.; Nurti, R.; Monge, I.; Rigotti, E.; Cantalupo, G.; Salviati, L.; Tucci, S.; Pellegrini, F.; Molinaro, G.; Lupi, F.; Tonin, P.; Pasini, A.; Campostrini, N.; Ion Popa, F.; Teofoli, F.; Vincenzi, M.; Camilot, M.; Piacentini, G.; Bordugo, A. Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience. Mol. Genet. Metab. Rep., 2020, 24, 100632.
[http://dx.doi.org/10.1016/j.ymgmr.2020.100632] [PMID: 32793418]

Zytkovicz, T.H.; Fitzgerald, E.F.; Marsden, D.; Larson, C.A.; Shih, V.E.; Johnson, D.M.; Strauss, A.W.; Comeau, A.M.; Eaton, R.B.; Grady, G.F. Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: A two-year summary from the new england newborn screening program. Clin. Chem., 2001, 47(11), 1945-1955.
[http://dx.doi.org/10.1093/clinchem/47.11.1945] [PMID: 11673361]

Andersen, L. W.; Mackenhauer, J.; Roberts, J. C.; Berg, K. M.; Cocchi, M. N.; Donnino, M. W. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc, 2013, 88(10), 1127-1140.

Fitzsimons, P.E.; Alston, C.L.; Bonnen, P.E.; Hughes, J.; Crushell, E.; Geraghty, M.T.; Tetreault, M.; O’Reilly, P.; Twomey, E.; Sheikh, Y.; Walsh, R.; Waterham, H.R.; Ferdinandusse, S.; Wanders, R.J.A.; Taylor, R.W.; Pitt, J.J.; Mayne, P.D. Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Am. J. Med. Genet. A., 2018, 176(5), 1115-1127.
[http://dx.doi.org/10.1002/ajmg.a.38658] [PMID: 29575569]

Ibrahim, A.Z.; Thirumal Kumar, D.; Abunada, T.; Younes, S.; George Priya Doss, C.; Zaki, O.K.; Zayed, H. Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia. Mol. Genet. Metab. Rep., 2020, 25, 100645.
[http://dx.doi.org/10.1016/j.ymgmr.2020.100645] [PMID: 32995289]

Aboulmaouahib, B.; Kastenmüller, G.; Suhre, K.; Zöllner, S.; Weissensteiner, H.; Prehn, C.; Adamski, J.; Gieger, C.; Wang-Sattler, R.; Lichtner, P.; Strauch, K.; Flaquer, A. First mitochondrial genome-wide association study with metabolomics. Hum. Mol. Genet., 2022, 31(19), 3367-3376.
[http://dx.doi.org/10.1093/hmg/ddab312] [PMID: 34718574]

Mai, M.; Tönjes, A.; Kovacs, P.; Stumvoll, M.; Fiedler, G.M.; Leichtle, A.B. Serum levels of acylcarnitines are altered in prediabetic conditions. PLoS One, 2013, 8(12), e82459.
[http://dx.doi.org/10.1371/journal.pone.0082459] [PMID: 24358186]

Hirano, M.; Emmanuele, V.; Quinzii, C.M. Emerging therapies for mitochondrial diseases. Essays Biochem., 2018, 62(3), 467-481.
[http://dx.doi.org/10.1042/EBC20170114] [PMID: 29980632]

El-Hattab, A.W.; Zarante, A.M.; Almannai, M.; Scaglia, F. Therapies for mitochondrial diseases and current clinical trials. Mol. Genet. Metab., 2017, 122(3), 1-9.
[http://dx.doi.org/10.1016/j.ymgme.2017.09.009] [PMID: 28943110]

Hidalgo-Gutiérrez, A.; González-García, P.; Díaz-Casado, M.E.; Barriocanal-Casado, E.; López-Herrador, S.; Quinzii, C.M.; López, L.C. Metabolic targets of coenzyme Q10 in mitochondria. Antioxidants, 2021, 10(4), 520.
[http://dx.doi.org/10.3390/antiox10040520] [PMID: 33810539]

Potgieter, M.; Pretorius, E.; Pepper, M.S. Primary and secondary coenzyme Q10 deficiency: The role of therapeutic supplementation. Nutr. Rev., 2013, 71(3), 180-188.
[http://dx.doi.org/10.1111/nure.12011] [PMID: 23452285]

Klopstock, T.; Yu-Wai-Man, P.; Dimitriadis, K.; Rouleau, J.; Heck, S.; Bailie, M.; Atawan, A.; Chattopadhyay, S.; Schubert, M.; Garip, A.; Kernt, M.; Petraki, D.; Rummey, C.; Leinonen, M.; Metz, G.; Griffiths, P.G.; Meier, T.; Chinnery, P.F. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain, 2011, 134(9), 2677-2686.
[http://dx.doi.org/10.1093/brain/awr170] [PMID: 21788663]

Klopstock, T.; Metz, G.; Yu-Wai-Man, P.; Büchner, B.; Gallenmüller, C.; Bailie, M.; Nwali, N.; Griffiths, P.G.; von Livonius, B.; Reznicek, L.; Rouleau, J.; Coppard, N.; Meier, T.; Chinnery, P.F. Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain, 2013, 136(2), e230-e230.
[http://dx.doi.org/10.1093/brain/aws279] [PMID: 23388409]

Rudolph, G.; Dimitriadis, K.; Büchner, B.; Heck, S.; Al-Tamami, J.; Seidensticker, F.; Rummey, C.; Leinonen, M.; Meier, T.; Klopstock, T. Effects of idebenone on color vision in patients with leber hereditary optic neuropathy. J. Neuroophthalmol., 2013, 33(1), 30-36.
[http://dx.doi.org/10.1097/WNO.0b013e318272c643] [PMID: 23263355]

Blanchet, L.; Smeitink, J.A.M.; van Emst - de Vries, S.E.; Vogels, C.; Pellegrini, M.; Jonckheere, A.I.; Rodenburg, R.J.T.; Buydens, L.M.C.; Beyrath, J.; Willems, P.H.G.M.; Koopman, W.J.H. Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning. Sci. Rep., 2015, 5(1), 8035.
[http://dx.doi.org/10.1038/srep08035] [PMID: 25620325]

Pfeffer, G.; Majamaa, K.; Turnbull, D.M.; Thorburn, D.; Chinnery, P.F. Treatment for mitochondrial disorders. Cochrane Database Syst. Rev., 2012, 2012(4), CD004426.
[PMID: 22513923]

Singh, A.; Faccenda, D.; Campanella, M. Pharmacological advances in mitochondrial therapy. EBioMedicine, 2021, 65, 103244.
[http://dx.doi.org/10.1016/j.ebiom.2021.103244] [PMID: 33647769]

Shrader, W.D.; Amagata, A.; Barnes, A.; Enns, G.M.; Hinman, A.; Jankowski, O.; Kheifets, V.; Komatsuzaki, R.; Lee, E.; Mollard, P.; Murase, K.; Sadun, A.A.; Thoolen, M.; Wesson, K.; Miller, G. α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg. Med. Chem. Lett., 2011, 21(12), 3693-3698.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.085] [PMID: 21600768]

Chen, X.; Sun, L.G.; Zhao, Y. NCMCMDA: MiRNA–disease association prediction through neighborhood constraint matrix completion. Brief. Bioinform., 2021, 22(1), 485-496.
[http://dx.doi.org/10.1093/bib/bbz159] [PMID: 31927572]

Janssen, M.C.H.; Koene, S.; de Laat, P.; Hemelaar, P.; Pickkers, P.; Spaans, E.; Beukema, R.; Beyrath, J.; Groothuis, J.; Verhaak, C.; Smeitink, J. The KHENERGY study: Safety and efficacy of KH 176 in mitochondrial m.3243A>G spectrum disorders. Clin. Pharmacol. Ther., 2019, 105(1), 101-111.
[http://dx.doi.org/10.1002/cpt.1197] [PMID: 30058726]

Smeitink, J.; van Maanen, R.; de Boer, L.; Ruiterkamp, G.; Renkema, H. A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms (“KHENERGYC”). BMC Neurol., 2022, 22(1), 158.
[http://dx.doi.org/10.1186/s12883-022-02685-3] [PMID: 35477351]

Marangon, K.; Devaraj, S.; Tirosh, O.; Packer, L.; Jialal, I. Comparison of the effect of α-lipoic acid and α-tocopherol supplementation on measures of oxidative stress. Free Radic. Biol. Med., 1999, 27(9-10), 1114-1121.
[http://dx.doi.org/10.1016/S0891-5849(99)00155-0] [PMID: 10569644]

Parikh, S.; Saneto, R.; Falk, M.J.; Anselm, I.; Cohen, B.H.; Haas, R.; Medicine Society, T.M. A modern approach to the treatment of mitochondrial disease. Curr. Treat. Options Neurol., 2009, 11(6), 414-430.
[http://dx.doi.org/10.1007/s11940-009-0046-0] [PMID: 19891905]

Anthony, R.M.; MacLeay, J.M.; Gross, K.L. Alpha-lipoic acid as a nutritive supplement for humans and animals: An overview of its use in dog food. Animals (Basel), 2021, 11(5), 1454.
[http://dx.doi.org/10.3390/ani11051454] [PMID: 34069383]

Salehi, B.; Berkay Yılmaz, Y.; Antika, G.; Boyunegmez Tumer, T.; Fawzi Mahomoodally, M.; Lobine, D.; Akram, M.; Riaz, M.; Capanoglu, E.; Sharopov, F.; Martins, N.; Cho, W.C.; Sharifi-Rad, J. Insights on the use of α-lipoic acid for therapeutic purposes. Biomolecules, 2019, 9(8), 356.
[http://dx.doi.org/10.3390/biom9080356] [PMID: 31405030]

Tarnopolsky, M.A. The mitochondrial cocktail: Rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv. Drug Deliv. Rev., 2008, 60(13-14), 1561-1567.
[http://dx.doi.org/10.1016/j.addr.2008.05.001] [PMID: 18647623]

Kastaniotis, A.J.; Autio, K.J.R.; R Nair, R. Mitochondrial fatty acids and neurodegenerative disorders. Neuroscientist, 2021, 27(2), 143-158.
[http://dx.doi.org/10.1177/1073858420936162] [PMID: 32644907]

Sato, Y.; Nakagawa, M.; Higuchi, I.; Osame, M.; Naito, E.; Oizumi, K. Mitochondrial myopathy and familial thiamine deficiency. Muscle Nerve, 2000, 23(7), 1069-1075.
[http://dx.doi.org/10.1002/1097-4598(200007)23:7<1069::AID-MUS9>3.0.CO;2-0] [PMID: 10883001]

Mermigkis, C.; Bouloukaki, I.; Mastorodemos, V.; Plaitakis, A.; Alogdianakis, V.; Siafakas, N.; Schiza, S. Medical treatment with thiamine, coenzyme Q, vitamins E and C, and carnitine improved obstructive sleep apnea in an adult case of Leigh disease. Sleep Breath., 2013, 17(4), 1129-1135.
[http://dx.doi.org/10.1007/s11325-013-0816-5] [PMID: 23389837]

Berlin, S.; Goette, A.; Summo, L.; Lossie, J.; Gebauer, A.; Al-Saady, N.; Calo, L.; Naccarelli, G.; Schunck, W.H.; Fischer, R.; Camm, A.J.; Dobrev, D. Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study. Int. J. Cardiol. Heart Vasc., 2020, 29, 100573.
[http://dx.doi.org/10.1016/j.ijcha.2020.100573] [PMID: 32685659]

Whitaker, R.M.; Corum, D.; Beeson, C.C.; Schnellmann, R.G. Mitochondrial biogenesis as a pharmacological target: A new approach to acute and chronic diseases. Annu. Rev. Pharmacol. Toxicol., 2016, 56(1), 229-249.
[http://dx.doi.org/10.1146/annurev-pharmtox-010715-103155] [PMID: 26566156]

Giordano, C.; Iommarini, L.; Giordano, L.; Maresca, A.; Pisano, A.; Valentino, M.L.; Caporali, L.; Liguori, R.; Deceglie, S.; Roberti, M.; Fanelli, F.; Fracasso, F.; Ross-Cisneros, F.N.; D’Adamo, P.; Hudson, G.; Pyle, A.; Yu-Wai-Man, P.; Chinnery, P.F.; Zeviani, M.; Salomao, S.R.; Berezovsky, A.; Belfort, R., Jr; Ventura, D.F.; Moraes, M.; Moraes Filho, M.; Barboni, P.; Sadun, F.; De Negri, A.; Sadun, A.A.; Tancredi, A.; Mancini, M.; d’Amati, G.; Loguercio Polosa, P.; Cantatore, P.; Carelli, V. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy. Brain, 2014, 137(2), 335-353.
[http://dx.doi.org/10.1093/brain/awt343] [PMID: 24369379]

Steele, H.; Gomez-Duran, A.; Pyle, A.; Hopton, S.; Newman, J.; Stefanetti, R.J.; Charman, S.J.; Parikh, J.D.; He, L.; Viscomi, C.; Jakovljevic, D.G.; Hollingsworth, K.G.; Robinson, A.J.; Taylor, R.W.; Bottolo, L.; Horvath, R.; Chinnery, P.F. Metabolic effects of bezafibrate in mitochondrial disease. EMBO Mol. Med., 2020, 12(3), e11589.
[http://dx.doi.org/10.15252/emmm.201911589] [PMID: 32107855]

Reisman, S.A.; Gahir, S.S.; Lee, C.Y.I.; Proksch, J.W.; Sakamoto, M.; Ward, K.W. Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates. Drug Des. Devel. Ther., 2019, 13, 1259-1270.
[http://dx.doi.org/10.2147/DDDT.S193889] [PMID: 31118567]

Russell, O.M.; Gorman, G.S.; Lightowlers, R.N.; Turnbull, D.M. Mitochondrial diseases: Hope for the future. Cell, 2020, 181(1), 168-188.
[http://dx.doi.org/10.1016/j.cell.2020.02.051] [PMID: 32220313]

Bishop, D.J.; Botella, J.; Genders, A.J.; Lee, M.J.C.; Saner, N.J.; Kuang, J.; Yan, X.; Granata, C. High-intensity exercise and mitochondrial biogenesis: Current controversies and future research directions. Physiology, 2019, 34(1), 56-70.
[http://dx.doi.org/10.1152/physiol.00038.2018] [PMID: 30540234]

Tarnopolsky, M.A. Exercise as a therapeutic strategy for primary mitochondrial cytopathies. J. Child Neurol., 2014, 29(9), 1225-1234.
[http://dx.doi.org/10.1177/0883073814538512] [PMID: 25008908]

Schaefer, P.M.; Rathi, K.; Butic, A.; Tan, W.; Mitchell, K.; Wallace, D.C. Mitochondrial mutations alter endurance exercise response and determinants in mice. Proc. Natl. Acad. Sci. USA, 2022, 119(18), e2200549119.
[http://dx.doi.org/10.1073/pnas.2200549119] [PMID: 35482926]

Chen, L.; Qin, Y.; Liu, B.; Gao, M.; Li, A.; Li, X.; Gong, G. PGC-1α-mediated mitochondrial quality control: Molecular mechanisms and implications for heart failure. Front. Cell Dev. Biol., 2022, 10, 871357.
[http://dx.doi.org/10.3389/fcell.2022.871357]

Scarpulla, R.C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev., 2008, 88(2), 611-638.
[http://dx.doi.org/10.1152/physrev.00025.2007] [PMID: 18391175]

Hong, S.; Kim, S.; Kim, K.; Lee, H. Clinical approaches for mitochondrial diseases. Cells, 2023, 12(20), 2494.
[http://dx.doi.org/10.3390/cells12202494] [PMID: 37887337]

Tiberi, J.; Segatto, M.; Fiorenza, M.T.; La Rosa, P. Apparent opportunities and hidden pitfalls: The conflicting results of restoring nrf2-regulated redox metabolism in friedreich’s ataxia pre-clinical models and clinical trials. Biomedicines, 2023, 11(5), 1293.
[http://dx.doi.org/10.3390/biomedicines11051293] [PMID: 37238963]

Wang, L.; Shan, H.; Wang, B.; Wang, N.; Zhou, Z.; Pan, C.; Wang, F. Puerarin attenuates osteoarthritis via upregulating AMP-activated protein kinase/proliferator-activated receptor-γ coactivator-1 signaling pathway in osteoarthritis rats. Pharmacology, 2018, 102(3-4), 117-125.
[http://dx.doi.org/10.1159/000490418] [PMID: 29961054]

Puigserver, P.; Spiegelman, B.M. Peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC-1 α): Transcriptional coactivator and metabolic regulator. Endocr. Rev., 2003, 24(1), 78-90.
[http://dx.doi.org/10.1210/er.2002-0012] [PMID: 12588810]

Viscomi, C.; Bottani, E.; Civiletto, G.; Cerutti, R.; Moggio, M.; Fagiolari, G.; Schon, E.A.; Lamperti, C.; Zeviani, M. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. Cell Metab., 2011, 14(1), 80-90.
[http://dx.doi.org/10.1016/j.cmet.2011.04.011] [PMID: 21723506]

Dillon, L.M.; Hida, A.; Garcia, S.; Prolla, T.A.; Moraes, C.T. Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse. PLoS One, 2012, 7(9), e44335.
[http://dx.doi.org/10.1371/journal.pone.0044335] [PMID: 22962610]

Fernandez-Marcos, P.J.; Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr., 2011, 93(4), 884S-890S.
[http://dx.doi.org/10.3945/ajcn.110.001917] [PMID: 21289221]

Yatsuga, S.; Suomalainen, A. Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice. Hum. Mol. Genet., 2012, 21(3), 526-535.
[http://dx.doi.org/10.1093/hmg/ddr482] [PMID: 22012983]

Jeppesen, T.D.; Schwartz, M.; Olsen, D.B.; Wibrand, F.; Krag, T.; Dunø, M.; Hauerslev, S.; Vissing, J. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain, 2006, 129(12), 3402-3412.
[http://dx.doi.org/10.1093/brain/awl149] [PMID: 16815877]

Corton, J.M.; Gillespie, J.G.; Hawley, S.A.; Hardie, D.G. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem., 1995, 229(2), 558-565.
[http://dx.doi.org/10.1111/j.1432-1033.1995.tb20498.x] [PMID: 7744080]

Golubitzky, A.; Dan, P.; Weissman, S.; Link, G.; Wikstrom, J.D.; Saada, A. Screening for active small molecules in mitochondrial complex I deficient patient’s fibroblasts, reveals AICAR as the most beneficial compound. PLoS One, 2011, 6(10), e26883.
[http://dx.doi.org/10.1371/journal.pone.0026883] [PMID: 22046392]

El-Mir, M.Y.; Nogueira, V.; Fontaine, E.; Avéret, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem., 2000, 275(1), 223-228.
[http://dx.doi.org/10.1074/jbc.275.1.223] [PMID: 10617608]

Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J., 2000, 348(3), 607-614.
[http://dx.doi.org/10.1042/bj3480607] [PMID: 10839993]

Marini, C.; Cossu, V.; Bauckneht, M.; Lanfranchi, F.; Raffa, S.; Orengo, A.M.; Ravera, S.; Bruno, S.; Sambuceti, G. Metformin and cancer glucose metabolism: At the bench or at the bedside? Biomolecules, 2021, 11(8), 1231.
[http://dx.doi.org/10.3390/biom11081231] [PMID: 34439897]

Madiraju, A.K.; Erion, D.M.; Rahimi, Y.; Zhang, X.M.; Braddock, D.T.; Albright, R.A.; Prigaro, B.J.; Wood, J.L.; Bhanot, S.; MacDonald, M.J.; Jurczak, M.J.; Camporez, J.P.; Lee, H.Y.; Cline, G.W.; Samuel, V.T.; Kibbey, R.G.; Shulman, G.I. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature, 2014, 510(7506), 542-546.
[http://dx.doi.org/10.1038/nature13270] [PMID: 24847880]

Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624]

Kra, G.; Daddam, J.R.; Gabay, H.; Yosefi, S.; Zachut, M. Antioxidant resveratrol increases lipolytic and reduces lipogenic gene expression under in vitro heat stress conditions in dedifferentiated adipocyte-derived progeny cells from dairy cows. Antioxidants, 2021, 10(6), 905.
[http://dx.doi.org/10.3390/antiox10060905] [PMID: 34205039]

Mizuguchi, Y.; Hatakeyama, H.; Sueoka, K.; Tanaka, M.; Goto, Y. Low dose resveratrol ameliorates mitochondrial respiratory dysfunction and enhances cellular reprogramming. Mitochondrion, 2017, 34, 43-48.
[http://dx.doi.org/10.1016/j.mito.2016.12.006] [PMID: 28093354]

De Paepe, B.; Vandemeulebroecke, K.; Smet, J.; Vanlander, A.; Seneca, S.; Lissens, W.; Van Hove, J.L.K.; Deschepper, E.; Briones, P.; Van Coster, R. Effect of resveratrol on cultured skin fibroblasts from patients with oxidative phosphorylation defects. Phytother. Res., 2014, 28(2), 312-316.
[http://dx.doi.org/10.1002/ptr.4988] [PMID: 23620374]

Tang, J.X.; Thompson, K.; Taylor, R.W.; Oláhová, M. Mitochondrial OXPHOS biogenesis: Co-regulation of protein synthesis, import, and assembly pathways. Int. J. Mol. Sci., 2020, 21(11), 3820.
[http://dx.doi.org/10.3390/ijms21113820] [PMID: 32481479]

Zhang, Y.; Xu, H. Translational regulation of mitochondrial biogenesis. Biochem. Soc. Trans., 2016, 44(6), 1717-1724.
[http://dx.doi.org/10.1042/BST20160071C] [PMID: 27913682]

Sa, B.K.; Kim, C.; Kim, M.B.; Hwang, J.K. Panduratin A prevents tumor necrosis factor-alpha-induced muscle atrophy in L6 rat skeletal muscle cells. J. Med. Food, 2017, 20(11), 1047-1054.
[http://dx.doi.org/10.1089/jmf.2017.3970] [PMID: 28933980]

Tengan, C.H.; Moraes, C.T. NO control of mitochondrial function in normal and transformed cells. Biochim. Biophys. Acta Bioenerg., 2017, 1858(8), 573-581.
[http://dx.doi.org/10.1016/j.bbabio.2017.02.009] [PMID: 28216426]

Bonaldo, P.; Sandri, M. Cellular and molecular mechanisms of muscle atrophy. Dis. Model. Mech., 2013, 6(1), 25-39.
[http://dx.doi.org/10.1242/dmm.010389] [PMID: 23268536]

Kim, M.B.; Kim, T.; Kim, C.; Hwang, J.K. Standardized Kaempferia parviflora extract enhances exercise performance through activation of mitochondrial biogenesis. J. Med. Food, 2018, 21(1), 30-38.
[http://dx.doi.org/10.1089/jmf.2017.3989] [PMID: 29125913]

Vaughan, R.A.; Mermier, C.M.; Bisoffi, M.; Trujillo, K.A.; Conn, C.A. Dietary stimulators of the PGC-1 superfamily and mitochondrial biosynthesis in skeletal muscle. A mini-review. J. Physiol. Biochem., 2014, 70(1), 271-284.
[http://dx.doi.org/10.1007/s13105-013-0301-4] [PMID: 24338337]

Tatsuta, T.; Langer, T. Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J., 2008, 27(2), 306-314.
[http://dx.doi.org/10.1038/sj.emboj.7601972] [PMID: 18216873]

Pellegrino, M.W.; Nargund, A.M.; Haynes, C.M. Signaling the mitochondrial unfolded protein response. Biochimica et Biophysica Acta (BBA)-. Molecular Cell Research, 2013, 1833, 410-416.

Sugiura, A.; McLelland, G.L.; Fon, E.A.; McBride, H.M. A new pathway for mitochondrial quality control: Mitochondrial-derived vesicles. EMBO J., 2014, 33(19), 2142-2156.
[http://dx.doi.org/10.15252/embj.201488104] [PMID: 25107473]

Wredenberg, A.; Wibom, R.; Wilhelmsson, H.; Graff, C.; Wiener, H.H.; Burden, S.J.; Oldfors, A.; Westerblad, H.; Larsson, N.G. Increased mitochondrial mass in mitochondrial myopathy mice. Proc. Natl. Acad. Sci. USA, 2002, 99(23), 15066-15071.
[http://dx.doi.org/10.1073/pnas.232591499] [PMID: 12417746]

Puigserver, P.; Wu, Z.; Park, C.W.; Graves, R.; Wright, M.; Spiegelman, B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell, 1998, 92(6), 829-839.
[http://dx.doi.org/10.1016/S0092-8674(00)81410-5] [PMID: 9529258]

Scarpulla, R. C. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta, 2002, 1-14.

Khan, N. A.; Nikkanen, J.; Yatsuga, S.; Jackson, C.; Wang, L.; Pradhan, S.; Kivelä, R.; Pessia, A.; Velagapudi, V.; Suomalainen, A. mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metabolism, 2017, 26, 419-428.

Johnson, S.C.; Kaeberlein, M. Rapamycin in aging and disease: Maximizing efficacy while minimizing side effects. Oncotarget, 2016, 7(29), 44876-44878.
[http://dx.doi.org/10.18632/oncotarget.10381] [PMID: 27384492]

Rahman, M.A.; Akter, S.; Dorotea, D.; Mazumder, A.; Uddin, M.N.; Hannan, M.A.; Hossen, M.J.; Ahmed, M.S.; Kim, W.; Kim, B.; Uddin, M.J. Renoprotective potentials of small molecule natural products targeting mitochondrial dysfunction. Front. Pharmacol., 2022, 13, 925993.
[http://dx.doi.org/10.3389/fphar.2022.925993] [PMID: 35910356]

Jacoby, E.; Bar-Yosef, O.; Gruber, N.; Lahav, E.; Varda-Bloom, N.; Bolkier, Y.; Bar, D.; Blumkin, M.B.Y.; Barak, S.; Eisenstein, E.; Ahonniska-Assa, J.; Silberg, T.; Krasovsky, T.; Bar, O.; Erez, N.; Bielorai, B.; Golan, H.; Dekel, B.; Besser, M.J.; Pozner, G.; Khoury, H.; Jacobs, A.; Campbell, J.; Herskovitz, E.; Sher, N.; Yivgi-Ohana, N.; Anikster, Y.; Toren, A. Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes. Sci. Transl. Med., 2022, 14(676), eabo3724.
[http://dx.doi.org/10.1126/scitranslmed.abo3724] [PMID: 36542693]

Emani, S.M.; McCully, J.D. Mitochondrial transplantation: Applications for pediatric patients with congenital heart disease. Transl. Pediatr., 2018, 7(2), 169-175.
[http://dx.doi.org/10.21037/tp.2018.02.02] [PMID: 29770298]

Rossi, A.; Asthana, A.; Riganti, C.; Sedrakyan, S.; Byers, L.N.; Robertson, J.; Senger, R.S.; Montali, F.; Grange, C.; Dalmasso, A.; Porporato, P.E.; Palles, C.; Thornton, M.E.; Da Sacco, S.; Perin, L.; Ahn, B.; McCully, J.; Orlando, G.; Bussolati, B. Mitochondria transplantation mitigates damage in an in vitro model of renal tubular injury and in an ex vivo model of DCD renal transplantation. Ann. Surg., 2023, 278(6), e1313-e1326.
[http://dx.doi.org/10.1097/SLA.0000000000006005] [PMID: 37450698]

Alemany, V.S.; Nomoto, R.; Saeed, M.Y.; Celik, A.; Regan, W.L.; Matte, G.S.; Recco, D.P.; Emani, S.M.; Del Nido, P.J.; McCully, J.D. Mitochondrial transplantation preserves myocardial function and viability in pediatric and neonatal pig hearts donated after circulatory death. J. Thorac. Cardiovasc. Surg., 2023, 167(1), e6-e21.
[PMID: 37211245]

Guariento, A.; Piekarski, B.L.; Doulamis, I.P.; Blitzer, D.; Ferraro, A.M.; Harrild, D.M.; Zurakowski, D.; del Nido, P.J.; McCully, J.D.; Emani, S.M. Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg., 2021, 162(3), 992-1001.
[http://dx.doi.org/10.1016/j.jtcvs.2020.10.151] [PMID: 33349443]

Wai, T.; Ao, A.; Zhang, X.; Cyr, D.; Dufort, D.; Shoubridge, E.A. The role of mitochondrial DNA copy number in mammalian fertility. Biol. Reprod., 2010, 83(1), 52-62.
[http://dx.doi.org/10.1095/biolreprod.109.080887] [PMID: 20130269]

Somuncu, B.; Ekmekcioglu, A.; Antmen, F.M.; Ertuzun, T.; Deniz, E.; Keskin, N.; Park, J.; Yazici, I.E.; Simsek, B.; Erman, B.; Yin, W.; Erman, B.; Muftuoglu, M. Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth. PLoS One, 2022, 17(6), e0268391.
[http://dx.doi.org/10.1371/journal.pone.0268391] [PMID: 35657956]

Bacman, S.R.; Gammage, P.; Minczuk, M.; Moraes, C.T. Manipulation of mitochondrial genes and mtDNA heteroplasmy; Elsevier, 2020, pp. 441-487.
[http://dx.doi.org/10.1016/bs.mcb.2019.12.004]

Falabella, M.; Minczuk, M.; Hanna, M.G.; Viscomi, C.; Pitceathly, R.D.S. Gene therapy for primary mitochondrial diseases: Experimental advances and clinical challenges. Nat. Rev. Neurol., 2022, 18(11), 689-698.
[http://dx.doi.org/10.1038/s41582-022-00715-9] [PMID: 36257993]

Barrera-Paez, J.D.; Moraes, C.T. Mitochondrial genome engineering coming-of-age. Trends Genet., 2022, 38(8), 869-880.
[http://dx.doi.org/10.1016/j.tig.2022.04.011]

Vigne, E.; Dedieu, J-F.; Brie, A.; Gillardeaux, A.; Briot, D.; Benihoud, K.; Latta-Mahieu, M.; Saulnier, P.; Perricaudet, M.; Yeh, P. Genetic manipulations of adenovirus type 5 fiber resulting in liver tropism attenuation. Gene Ther., 2003, 10(2), 153-162.
[http://dx.doi.org/10.1038/sj.gt.3301845] [PMID: 12571644]

Miyagawa, Y.; Marino, P.; Verlengia, G.; Uchida, H.; Goins, W.F.; Yokota, S.; Geller, D.A.; Yoshida, O.; Mester, J.; Cohen, J.B.; Glorioso, J.C. Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity. Proc. Natl. Acad. Sci. USA, 2015, 112(13), E1632-E1641.
[http://dx.doi.org/10.1073/pnas.1423556112] [PMID: 25775541]

Orefice, N.S. Development of new strategies using extracellular vesicles loaded with exogenous nucleic acid. Pharmaceutics, 2020, 12(8), 705.
[http://dx.doi.org/10.3390/pharmaceutics12080705] [PMID: 32722622]

Vignal, C.; Uretsky, S.; Fitoussi, S.; Galy, A.; Blouin, L.; Girmens, J.F.; Bidot, S.; Thomasson, N.; Bouquet, C.; Valero, S.; Meunier, S.; Combal, J.P.; Gilly, B.; Katz, B.; Sahel, J.A. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy. Ophthalmology, 2018, 125(6), 945-947.
[http://dx.doi.org/10.1016/j.ophtha.2017.12.036] [PMID: 29426586]

Chang, J.C.; Ryan, M.R.; Stark, M.C.; Liu, S.; Purushothaman, P.; Bolan, F.; Johnson, C.A.; Champe, M.; Meng, H.; Lawlor, M.W.; Halawani, S.; Ngaba, L.V.; Lynch, D.R.; Davis, C.; Gonzalo-Gil, E.; Lutz, C.; Urbinati, F.; Medicherla, B.; Fonck, C. AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia. Mol. Ther. Methods Clin. Dev., 2024, 32(1), 101193.
[http://dx.doi.org/10.1016/j.omtm.2024.101193] [PMID: 38352270]

Begum, A.A.; Toth, I.; Hussein, W.M.; Moyle, P.M. Advances in targeted gene delivery. Curr. Drug Deliv., 2019, 16(7), 588-608.
[http://dx.doi.org/10.2174/1567201816666190529072914] [PMID: 31142250]

Gammage, P.A.; Gaude, E.; Van Haute, L.; Rebelo-Guiomar, P.; Jackson, C.B.; Rorbach, J.; Pekalski, M.L.; Robinson, A.J.; Charpentier, M.; Concordet, J.P.; Frezza, C.; Minczuk, M. Near-complete elimination of mutant mtDNA by iterative or dynamic dose- controlled treatment with mtZFNs. Nucleic Acids Res., 2016, 44(16), 7804-7816.
[http://dx.doi.org/10.1093/nar/gkw676] [PMID: 27466392]

Bacman, S.R.; Kauppila, J.H.K.; Pereira, C.V.; Nissanka, N.; Miranda, M.; Pinto, M.; Williams, S.L.; Larsson, N.G.; Stewart, J.B.; Moraes, C.T. MitoTALEN reduces mutant mtDNA load and restores tRNA^Ala levels in a mouse model of heteroplasmic mtDNA mutation. Nat. Med., 2018, 24(11), 1696-1700.
[http://dx.doi.org/10.1038/s41591-018-0166-8] [PMID: 30250143]

Gammage, P.A.; Viscomi, C.; Simard, M.L.; Costa, A.S.H.; Gaude, E.; Powell, C.A.; Van Haute, L.; McCann, B.J.; Rebelo-Guiomar, P.; Cerutti, R.; Zhang, L.; Rebar, E.J.; Zeviani, M.; Frezza, C.; Stewart, J.B.; Minczuk, M. Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nat. Med., 2018, 24(11), 1691-1695.
[http://dx.doi.org/10.1038/s41591-018-0165-9] [PMID: 30250142]

Hendel, A.; Fine, E.J.; Bao, G.; Porteus, M.H. Quantifying on- and off-target genome editing. Trends Biotechnol., 2015, 33(2), 132-140.
[http://dx.doi.org/10.1016/j.tibtech.2014.12.001] [PMID: 25595557]

Jo, A.; Ham, S.; Lee, G.H.; Lee, Y.I.; Kim, S.; Lee, Y.S.; Shin, J.H.; Lee, Y. Efficient mitochondrial genome editing by CRISPR/Cas9. BioMed Res. Int., 2015, 2015, 1-10.
[http://dx.doi.org/10.1155/2015/305716] [PMID: 26448933]

Prakash, R.; Kannan, A. Mitochondrial DNA modification by CRISPR/Cas system: Challenges and future direction. Prog. Mol. Biol. Transl. Sci., 2021, 178, 193-211.
[http://dx.doi.org/10.1016/bs.pmbts.2020.12.009] [PMID: 33685597]

Bayona-Bafaluy, M.P.; Blits, B.; Battersby, B.J.; Shoubridge, E.A.; Moraes, C.T. Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease. Proc. Natl. Acad. Sci. USA, 2005, 102(40), 14392-14397.
[http://dx.doi.org/10.1073/pnas.0502896102] [PMID: 16179392]

Tanaka, M.; Borgeld, H-J.; Zhang, J.; Muramatsu, S.; Gong, J-S.; Yoneda, M.; Maruyama, W.; Naoi, M.; Ibi, T.; Sahashi, K.; Shamoto, M.; Fuku, N.; Kurata, M.; Yamada, Y.; Nishizawa, K.; Akao, Y.; Ohishi, N.; Miyabayashi, S.; Umemoto, H.; Muramatsu, T.; Furukawa, K.; Kikuchi, A.; Nakano, I.; Ozawa, K.; Yagi, K. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci., 2002, 9(6 Pt 1), 534-541.
[PMID: 12372991]

Alexeyev, M.F.; Venediktova, N.; Pastukh, V.; Shokolenko, I.; Bonilla, G.; Wilson, G.L. Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther., 2008, 15(7), 516-523.
[http://dx.doi.org/10.1038/gt.2008.11] [PMID: 18256697]

Fukui, H.; Moraes, C.T. Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum. Mol. Genet., 2009, 18(6), 1028-1036.
[http://dx.doi.org/10.1093/hmg/ddn437] [PMID: 19095717]

Wang, X.; Pickrell, A.M.; Rossi, S.G.; Pinto, M.; Dillon, L.M.; Hida, A.; Rotundo, R.L.; Moraes, C.T. Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool. Hum. Mol. Genet., 2013, 22(19), 3976-3986.
[http://dx.doi.org/10.1093/hmg/ddt251] [PMID: 23760083]

Mutti, C.; Silva-Pinheiro, P.; Minczuk, M. Fixing the powerhouse: Genetic engineering of mitochondrial DNA. Biochemist, 2022, 44(4), 9-13.
[http://dx.doi.org/10.1042/bio_2022_120]

Bacman, S.R.; Williams, S.L.; Hernandez, D.; Moraes, C.T. Modulating mtDNA heteroplasmy by mitochondria-targeted restriction endonucleases in a ‘differential multiple cleavage-site’ model. Gene Ther., 2007, 14(18), 1309-1318.
[http://dx.doi.org/10.1038/sj.gt.3302981] [PMID: 17597792]

Wang, G.; Shimada, E.; Koehler, C.M.; Teitell, M.A. PNPASE and RNA trafficking into mitochondria. Biochim Biophys Acta., 2012, 1819, 998-1007.

Shepherd, D.L.; Hathaway, Q.A.; Pinti, M.V.; Nichols, C.E.; Durr, A.J.; Sreekumar, S.; Hughes, K.M.; Stine, S.M.; Martinez, I.; Hollander, J.M. Exploring the mitochondrial microRNA import pathway through polynucleotide phosphorylase (PNPase). J. Mol. Cell. Cardiol., 2017, 110, 15-25.
[http://dx.doi.org/10.1016/j.yjmcc.2017.06.012] [PMID: 28709769]

Sato, R.; Arai-Ichinoi, N.; Kikuchi, A.; Matsuhashi, T.; Numata-Uematsu, Y.; Uematsu, M.; Fujii, Y.; Murayama, K.; Ohtake, A.; Abe, T.; Kure, S. Novel biallelic mutations in thePNPT1 gene encoding a mitochondrial- RNA -import protein PNPASE cause delayed myelination. Clin. Genet., 2018, 93(2), 242-247.
[http://dx.doi.org/10.1111/cge.13068] [PMID: 28594066]

Wang, G.; Chen, H.W.; Oktay, Y.; Zhang, J.; Allen, E.L.; Smith, G.M.; Fan, K.C.; Hong, J.S.; French, S.W.; McCaffery, J.M.; Lightowlers, R.N.; Morse, H.C., III; Koehler, C.M.; Teitell, M.A. PNPASE regulates RNA import into mitochondria. Cell, 2010, 142(3), 456-467.
[http://dx.doi.org/10.1016/j.cell.2010.06.035] [PMID: 20691904]

Hussain, S.R.A.; Yalvac, M.E.; Khoo, B.; Eckardt, S.; McLaughlin, K.J. Adapting CRISPR/Cas9 system for targeting mitochondrial genome. Front. Genet., 2021, 12, 627050.
[http://dx.doi.org/10.3389/fgene.2021.627050] [PMID: 33889176]

Mok, B.Y.; de Moraes, M.H.; Zeng, J.; Bosch, D.E.; Kotrys, A.V.; Raguram, A.; Hsu, F.; Radey, M.C.; Peterson, S.B.; Mootha, V.K.; Mougous, J.D.; Liu, D.R. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature, 2020, 583(7817), 631-637.
[http://dx.doi.org/10.1038/s41586-020-2477-4] [PMID: 32641830]

Moraes, C.T.; Bacman, S.R.; Williams, S.L. Manipulating mitochondrial genomes in the clinic: playing by different rules. Trends Cell Biol., 2014, 24(4), 209-211.
[http://dx.doi.org/10.1016/j.tcb.2014.02.002] [PMID: 24679453]

Peranteau, W.H.; Flake, A.W. The future of in utero gene therapy. Mol. Diagn. Ther., 2020, 24(2), 135-142.
[http://dx.doi.org/10.1007/s40291-020-00445-y] [PMID: 32020561]

Sharma, H.; Singh, D.; Mahant, A.; Sohal, S.K.; Kesavan, A.K.; Samiksha Development of mitochondrial replacement therapy: A review. Heliyon, 2020, 6(9), e04643.
[http://dx.doi.org/10.1016/j.heliyon.2020.e04643] [PMID: 32984570]

Smeets, H.J.M. Preventing the transmission of mitochondrial DNA disorders: Selecting the good guys or kicking out the bad guys. Reprod. Biomed. Online, 2013, 27(6), 599-610.
[http://dx.doi.org/10.1016/j.rbmo.2013.08.007] [PMID: 24135157]

Tachibana, M.; Amato, P.; Sparman, M.; Woodward, J.; Sanchis, D.M.; Ma, H.; Gutierrez, N.M.; Tippner-Hedges, R.; Kang, E.; Lee, H.S.; Ramsey, C.; Masterson, K.; Battaglia, D.; Lee, D.; Wu, D.; Jensen, J.; Patton, P.; Gokhale, S.; Stouffer, R.; Mitalipov, S. Towards germline gene therapy of inherited mitochondrial diseases. Nature, 2013, 493(7434), 627-631.
[http://dx.doi.org/10.1038/nature11647] [PMID: 23103867]

Sendra, L.; García-Mares, A.; Herrero, M.J.; Aliño, S.F. Mitochondrial dna replacement techniques to prevent human mitochondrial diseases. Int. J. Mol. Sci., 2021, 22(2), 551.
[http://dx.doi.org/10.3390/ijms22020551] [PMID: 33430493]

Greenfield, A.; Braude, P.; Flinter, F.; Lovell-Badge, R.; Ogilvie, C.; Perry, A.C.F. Assisted reproductive technologies to prevent human mitochondrial disease transmission. Nat. Biotechnol., 2017, 35(11), 1059-1068.
[http://dx.doi.org/10.1038/nbt.3997] [PMID: 29121011]

Gorman, G.S.; McFarland, R.; Stewart, J.; Feeney, C.; Turnbull, D.M. Mitochondrial donation: From test tube to clinic. Lancet, 2018, 392(10154), 1191-1192.
[http://dx.doi.org/10.1016/S0140-6736(18)31868-3] [PMID: 30319102]

Aryamvally, A.; Myers, M.F.; Huang, T.; Slone, J.; Pilipenko, V.; Hartmann, J.E. Mitochondrial replacement therapy: Genetic counselors’ experiences, knowledge, and opinions. J. Genet. Couns., 2021, 30(3), 828-837.
[http://dx.doi.org/10.1002/jgc4.1382] [PMID: 33469959]

Fan, X-Y.; Yin, S.; Luo, S-M. SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy. Autophagy, 2022, 19(1), 363-364.
[PMID: 35574946]

Fan, X.Y.; Guo, L.; Chen, L.N.; Yin, S.; Wen, J.; Li, S.; Ma, J.Y.; Jing, T.; Jiang, M.X.; Sun, X.H.; Chen, M.; Wang, F.; Wang, Z.B.; Zhang, C.F.; Wang, X.H.; Ge, Z.J.; Hu, C.; Zeng, L.; Shen, W.; Sun, Q.Y.; Ou, X.H.; Luo, S.M. Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy. Nat. Biomed. Eng., 2022, 6(4), 339-350.
[http://dx.doi.org/10.1038/s41551-022-00881-7] [PMID: 35437313]

Hellebrekers, D.M.E.I.; Wolfe, R.; Hendrickx, A.T.M.; de Coo, I.F.M.; de Die, C.E.; Geraedts, J.P.M.; Chinnery, P.F.; Smeets, H.J.M. PGD and heteroplasmic mitochondrial DNA point mutations: A systematic review estimating the chance of healthy offspring. Hum. Reprod. Update, 2012, 18(4), 341-349.
[http://dx.doi.org/10.1093/humupd/dms008] [PMID: 22456975]

Poulton, J.; Steffann, J.; Burgstaller, J.; McFarland, R. 243rd ENMC international workshop: Developing guidelines for management of reproductive options for families with maternally inherited mtDNA disease, Amsterdam, the Netherlands, 22–24 March 2019. Neuromuscul. Disord., 2019, 29(9), 725-733.
[http://dx.doi.org/10.1016/j.nmd.2019.08.004] [PMID: 31501000]

Keshavan, N.; Minczuk, M.; Viscomi, C.; Rahman, S. Gene therapy for mitochondrial disorders. J. Inherit. Metab. Dis., 2024, 47(1), 145-175.
[http://dx.doi.org/10.1002/jimd.12699] [PMID: 38171948]