Mitochondrial Diseases: the Contribution of Organelle Stress Responses to Pathology

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2017 Aug 10

PMID 28792006

Citations 235

Authors

Anu Suomalainen

Brendan J Battersby

Affiliations

Soon will be listed here.

Abstract

Mitochondrial diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in mitochondrial protein synthesis and mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human mitochondrial diseases.

Citing Articles

Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.

Thayer J, Petersen J, Huang X, Hawrot J, Ramos D, Sekine S bioRxiv. 2025; .

PMID: 40027798 PMC: 11870511. DOI: 10.1101/2025.02.19.639160.

Mitochondrial base editing: from principle, optimization to application.

Tang J, Du K Cell Biosci. 2025; 15(1):9.

PMID: 39856740 PMC: 11762502. DOI: 10.1186/s13578-025-01351-8.

Mitochondrial diseases: from molecular mechanisms to therapeutic advances.

Wen H, Deng H, Li B, Chen J, Zhu J, Zhang X Signal Transduct Target Ther. 2025; 10(1):9.

PMID: 39788934 PMC: 11724432. DOI: 10.1038/s41392-024-02044-3.

Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.

El Fissi N, Rosenberger F, Chang K, Wilhalm A, Barton-Owen T, Hansen F Nat Commun. 2024; 15(1):10719.

PMID: 39715749 PMC: 11666730. DOI: 10.1038/s41467-024-55559-2.

Mitochondrial Transplantation Ameliorates Pulmonary Fibrosis by Suppressing Myofibroblast Activation.

Lee S, Yu S, Kim I, Kang Y, Kim Y, Yeo J Int J Mol Sci. 2024; 25(23).

PMID: 39684495 PMC: 11641484. DOI: 10.3390/ijms252312783.

References

Pagliarini D, Calvo S, Chang B, Sheth S, Vafai S, Ong S . A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008; 134(1):112-23. PMC: 2778844. DOI: 10.1016/j.cell.2008.06.016. View

Durieux J, Wolff S, Dillin A . The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011; 144(1):79-91. PMC: 3062502. DOI: 10.1016/j.cell.2010.12.016. View

Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z . Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell. 2011; 20(5):674-88. PMC: 3221282. DOI: 10.1016/j.ccr.2011.10.015. View

Sasarman F, Antonicka H, Shoubridge E . The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008; 17(23):3697-707. DOI: 10.1093/hmg/ddn265. View

Fan J, Ye J, Kamphorst J, Shlomi T, Thompson C, Rabinowitz J . Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 2014; 510(7504):298-302. PMC: 4104482. DOI: 10.1038/nature13236. View

Ahola-Erkkila S, Carroll C, Peltola-Mjosund K, Tulkki V, Mattila I, Seppanen-Laakso T . Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum Mol Genet. 2010; 19(10):1974-84. DOI: 10.1093/hmg/ddq076. View

Bourdon A, Minai L, Serre V, Jais J, Sarzi E, Aubert S . Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007; 39(6):776-80. DOI: 10.1038/ng2040. View

Reczek C, Chandel N . ROS-dependent signal transduction. Curr Opin Cell Biol. 2014; 33:8-13. PMC: 4380867. DOI: 10.1016/j.ceb.2014.09.010. View

Galper J . Mitochondrial protein synthesis in HeLa cells. J Cell Biol. 1974; 60(3):755-63. PMC: 2109234. DOI: 10.1083/jcb.60.3.755. View

10.

Wanrooij S, Fuste J, Farge G, Shi Y, Gustafsson C, Falkenberg M . Human mitochondrial RNA polymerase primes lagging-strand DNA synthesis in vitro. Proc Natl Acad Sci U S A. 2008; 105(32):11122-7. PMC: 2516254. DOI: 10.1073/pnas.0805399105. View

11.

Nilsson R, Jain M, Madhusudhan N, Gustafsson Sheppard N, Strittmatter L, Kampf C . Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014; 5:3128. PMC: 4106362. DOI: 10.1038/ncomms4128. View

12.

Carroll C, Isohanni P, Poyhonen R, Euro L, Richter U, Brilhante V . Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy. J Med Genet. 2013; 50(3):151-9. DOI: 10.1136/jmedgenet-2012-101375. View

13.

Lewis S, Uchiyama L, Nunnari J . ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science. 2016; 353(6296):aaf5549. PMC: 5554545. DOI: 10.1126/science.aaf5549. View

14.

Konovalova S, Tyynismaa H . Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab. 2013; 108(4):206-11. DOI: 10.1016/j.ymgme.2013.01.010. View

15.

Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P . Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 1998; 93(6):973-83. DOI: 10.1016/s0092-8674(00)81203-9. View

16.

Arnaudo E, Dalakas M, Shanske S, Moraes C, DiMauro S, Schon E . Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet. 1991; 337(8740):508-10. DOI: 10.1016/0140-6736(91)91294-5. View

17.

Spelbrink J, Li F, Tiranti V, Nikali K, Yuan Q, Tariq M . Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001; 28(3):223-31. DOI: 10.1038/90058. View

18.

Suomalainen A . Therapy for mitochondrial disorders: little proof, high research activity, some promise. Semin Fetal Neonatal Med. 2011; 16(4):236-40. DOI: 10.1016/j.siny.2011.05.003. View

19.

Enriquez J, Chomyn A, Attardi G . MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and premature translation termination. Nat Genet. 1995; 10(1):47-55. DOI: 10.1038/ng0595-47. View

20.

Tyynismaa H, Sembongi H, Bokori-Brown M, Granycome C, Ashley N, Poulton J . Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number. Hum Mol Genet. 2004; 13(24):3219-27. DOI: 10.1093/hmg/ddh342. View