Mitochondrial translation defects and human disease

Abstract

In eukaryotic cells, mitochondria perform the essential function of producing cellular energy in the form of ATP via the oxidative phosphorylation system. This system is composed of 5 multimeric protein complexes of which 13 protein subunits are encoded by the mitochondrial genome: Complex I (7 subunits), Complex III (1 subunit), Complex IV (3 subunits), and Complex V (2 subunits). Effective mitochondrial translation is necessary to produce the protein subunits encoded by the mitochondrial genome (mtDNA). Defects in mitochondrial translation are known to cause a wide variety of clinical disease in humans with high-energy consuming organs generally most prominently affected. Here, we review several classes of disease resulting from defective mitochondrial translation including disorders with mitochondrial tRNA mutations, mitochondrial aminoacyl-tRNA synthetase disorders, mitochondrial rRNA mutations, and mitochondrial ribosomal protein disorders.

Keywords

Mitochondria / translation defect / tRNA / aminoacyl-tRNA synthetase / rRNA / ribosomal protein / mitochondrial disease / mtDNA

References

[1] Pagliarini DJ,Chang B,Vafai SB.A mitochondrial protein compendium elucidates complex I disease biology..Cell2008;134:112-23 PMCID:PMC2778844

[2] Priesnitz C.Pathways to balance mitochondrial translation and protein import..Genes Dev2018;32:1285-96 PMCID:PMC6169841

[3] Battersby BJ.Why translation counts for mitochondria - retrograde signalling links mitochondrial protein synthesis to mitochondrial biogenesis and cell proliferation..J Cell Sci2013;126:4331-8

[4] Smits P,van den Heuvel L.Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies..J Biomed Biotechnol2010;2010:737385 PMCID:PMC2854570

[5] Lightowlers RN,Chrzanowska-Lightowlers ZM.Mitochondrial protein synthesis: figuring the fundamentals, complexities and complications, of mammalian mitochondrial translation..FEBS Lett2014;588:2496-503 PMCID:PMC4099522

[6] Richter R,Dennerlein S,Lightowlers RN.Translation termination in human mitochondrial ribosomes..Biochem Soc Trans2010;38:1523-6

[7] Ban N,Cate JH,Dragon F.A new system for naming ribosomal proteins..Curr Opin Struct Biol2014;24:165-9 PMCID:PMC4358319

[8] Van Haute L,Powell CA,Nicholls TJ.Mitochondrial transcript maturation and its disorders..J Inherit Metab Dis2015;38:655-80 PMCID:PMC4493943

[9] Barchiesi A.Transcription, processing, and decay of mitochondrial RNA in health and disease..Int J Mol Sci2019;20: PMCID:PMC6540609

[10] Gonzalez-Serrano LE,Sissler M.When a common biological role does not imply common disease outcomes: disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases..J Biol Chem2019;294:5309-20 PMCID:PMC6462531

[11] Kobayashi Y,Tominaga K,Nihei K.A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes)..Biochem Biophys Res Commun1990;173:816-22

[12] Abbott JA,Robey-Bond SM.Transfer RNA and human disease..Front Genet2014;5:158 PMCID:PMC4042891

[13] Luo S,Zhang J,Slone J.Biparental inheritance of mitochondrial DNA in humans..Proc Natl Acad Sci U S A2018;115:13039-44 PMCID:PMC6304937

[14] Schwartz M.Paternal inheritance of mitochondrial DNA..N Engl J Med2002;347:576-80

[15] El-Hattab AW,Melas SF.Adam MP,Pagon RA.GeneReviews (R)..1993;Seattle (WA)

[16] DiMauro S.Adam MP,Pagon RA.Merrf..GeneReviews (R).1993;Seattle (WA)

[17] Sissler M,Westhof E.Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease..Trends Mol Med2017;23:693-708

[18] Boczonadi V,Horvath R.The role of tRNA synthetases in neurological and neuromuscular disorders..FEBS Lett2018;592:703-17 PMCID:PMC5873386

[19] Scheper GC,van Andel RJ,Sissler M.Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation..Nat Genet2007;39:534-9

[20] Konovalova S.Mitochondrial aminoacyl-tRNA synthetases in human disease..Mol Genet Metab2013;108:206-11

[21] Webb BD,Hagen JJ,Linderman MD.Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss..Hum Mutat2015;36:587-92 PMCID:PMC4439286

[22] Pierce SB,Lynch ED,Walsh T.Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome..Proc Natl Acad Sci U S A2011;108:6543-8 PMCID:PMC3081023

[23] Pierce SB,Michaelson-Cohen R,Lee MK.Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome..Am J Hum Genet2013;92:614-20 PMCID:PMC3617377

[24] Belostotsky R,Rinat C,Feinstein S.Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome..Am J Hum Genet2011;88:193-200 PMCID:PMC3035710

[25] Antonellis A,Sambuughin N,Abel A.Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V..Am J Hum Genet2003;72:1293-9 PMCID:PMC1180282

[26] McLaughlin HM,Liu C,Pehlivan D.Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy..Am J Hum Genet2010;87:560-6 PMCID:PMC2948804

[27] Santos-Cortez RL,Azeem Z,Pollock LM.Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89..Am J Hum Genet2013;93:132-40 PMCID:PMC3710764

[28] Ruzzenente B,Barcia G,Boddaert N.Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis..Hum Mutat2018;39:2047-59

[29] Ardissone A,Legati A,Barone R.KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature..Orphanet J Rare Dis2018;13:45 PMCID:PMC5883414

[30] Scheidecker S,Stoetzel C,Lannes B.Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy..Hum Mutat2019;40:1826-40

[31] Verrigni D,Di Nottia M,Bellacchio E.Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect..Clin Genet2017;91:918-23

[32] Kohda M,Kishita Y,Moriyama Y.A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies..PLoS Genet2016;12:e1005679 PMCID:PMC4704781

[33] Friederich MW,Powell CA,Kurolap A.Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder..Nat Commun2018;9:4065 PMCID:PMC6170436

[34] Fine AS,Kaufman ML.Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination..J Neurodev Disord2019;11:29 PMCID:PMC6913031

[35] D’Souza AR.Mitochondrial transcription and translation: overview..Essays Biochem2018;62:309-20 PMCID:PMC6056719

[36] Amunts A,Toots J,Ramakrishnan V.Ribosome. The structure of the human mitochondrial ribosome..Science2015;348:95-8 PMCID:PMC4501431

[37] Greber BJ,Leibundgut M,Aebersold R.Ribosome. The complete structure of the 55S mammalian mitochondrial ribosome..Science2015;348:303-8

[38] Hakli S,Sorri M.Mutations in the two ribosomal RNA genes in mitochondrial DNA among Finnish children with hearing impairment..BMC Med Genet2015;16:3 PMCID:PMC4410458

[39] Zhao H,Wang Q,Deng JH.Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family..Am J Hum Genet2004;74:139-52 PMCID:PMC1181901

[40] Kullar PJ,Gammage PA,Minczuk M.Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family..Brain2018;141:55-62 PMCID:PMC5837410

[41] Alila-Fersi O,Majdoub I,Mkaouar-Rebai E.Co segregation of the m.1555A>G mutation in the MT-RNR1 gene and mutations in MT-ATP6 gene in a family with dilated mitochondrial cardiomyopathy and hearing loss: a whole mitochondrial genome screening..Biochem Biophys Res Commun2017;484:71-8

[42] Bianco A,De Caro MF,De Bonis P.Leber’s hereditary optic neuropathy, intellectual disability and epilepsy presenting with variable penetrance associated to the m.3460G >A mutation and a heteroplasmic expansion of the microsatellite in MTRNR1 gene - case report..BMC Med Genet2018;19:129 PMCID:PMC6062935

[43] Liu Z,Li D,Li S.The novel mitochondrial 16S rRNA 2336T>C mutation is associated with hypertrophic cardiomyopathy..J Med Genet2014;51:176-84 PMCID:PMC3932983

[44] Lake NJ,Stroud DA,Ruzzenente B.Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and leigh syndrome..Am J Hum Genet2017;101:239-54 PMCID:PMC5544391

[45] Chen A,Guran T,Bayram Y.Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency..Hum Mol Genet2018;27:1913-26 PMCID:PMC5961111