Mitochondrial Genetics, Signalling and Stress Responses

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2025 Mar 11

PMID 40065146

Authors

Yasmine J Liu

Jonathan Sulc

Johan Auwerx

Affiliations

Soon will be listed here.

Abstract

Mitochondria are multifaceted organelles with crucial roles in energy generation, cellular signalling and a range of synthesis pathways. The study of mitochondrial biology is complicated by its own small genome, which is matrilineally inherited and not subject to recombination, and present in multiple, possibly different, copies. Recent methodological developments have enabled the analysis of mitochondrial DNA (mtDNA) in large-scale cohorts and highlight the far-reaching impact of mitochondrial genetic variation. Genome-editing techniques have been adapted to target mtDNA, further propelling the functional analysis of mitochondrial genes. Mitochondria are finely tuned signalling hubs, a concept that has been expanded by advances in methodologies for studying the function of mitochondrial proteins and protein complexes. Mitochondrial respiratory complexes are of dual genetic origin, requiring close coordination between mitochondrial and nuclear gene-expression systems (transcription and translation) for proper assembly and function, and recent findings highlight the importance of the mitochondria in this bidirectional signalling.

References

Suomalainen A, Nunnari J . Mitochondria at the crossroads of health and disease. Cell. 2024; 187(11):2601-2627. DOI: 10.1016/j.cell.2024.04.037. View

Murphy M, ONeill L . A break in mitochondrial endosymbiosis as a basis for inflammatory diseases. Nature. 2024; 626(7998):271-279. DOI: 10.1038/s41586-023-06866-z. View

Mottis A, Herzig S, Auwerx J . Mitocellular communication: Shaping health and disease. Science. 2019; 366(6467):827-832. DOI: 10.1126/science.aax3768. View

Picard M, Shirihai O . Mitochondrial signal transduction. Cell Metab. 2022; 34(11):1620-1653. PMC: 9692202. DOI: 10.1016/j.cmet.2022.10.008. View

Morgenstern M, Peikert C, Lubbert P, Suppanz I, Klemm C, Alka O . Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell Metab. 2021; 33(12):2464-2483.e18. PMC: 8664129. DOI: 10.1016/j.cmet.2021.11.001. View

Wallace D . Mitochondrial genetic medicine. Nat Genet. 2018; 50(12):1642-1649. DOI: 10.1038/s41588-018-0264-z. View

Mavraki E, Labrum R, Sergeant K, Alston C, Woodward C, Smith C . Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines. Eur J Hum Genet. 2022; 31(2):148-163. PMC: 9905091. DOI: 10.1038/s41431-022-01249-w. View

Elson J, Majamaa K, Howell N, Chinnery P . Associating mitochondrial DNA variation with complex traits. Am J Hum Genet. 2007; 80(2):378-82. PMC: 1785337. DOI: 10.1086/511652. View

Yonova-Doing E, Calabrese C, Gomez-Duran A, Schon K, Wei W, Karthikeyan S . An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank. Nat Genet. 2021; 53(7):982-993. PMC: 7611844. DOI: 10.1038/s41588-021-00868-1. View

10.

Lake N, Ma K, Liu W, Battle S, Laricchia K, Tiao G . Quantifying constraint in the human mitochondrial genome. Nature. 2024; 635(8038):390-397. PMC: 11646341. DOI: 10.1038/s41586-024-08048-x. View

11.

Hong Y, Battle S, Shi W, Puiu D, Pillalamarri V, Xie J . Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality. Nat Commun. 2023; 14(1):6113. PMC: 10542802. DOI: 10.1038/s41467-023-41785-7. View

12.

Stewart J, Chinnery P . The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet. 2015; 16(9):530-42. DOI: 10.1038/nrg3966. View

13.

Gupta R, Kanai M, Durham T, Tsuo K, McCoy J, Kotrys A . Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature. 2023; 620(7975):839-848. PMC: 10447254. DOI: 10.1038/s41586-023-06426-5. View

14.

Hagg S, Jylhava J, Wang Y, Czene K, Grassmann F . Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. Hum Genet. 2021; 140(6):849-861. PMC: 8099832. DOI: 10.1007/s00439-020-02249-w. View

15.

Wei W, Tuna S, Keogh M, Smith K, Aitman T, Beales P . Germline selection shapes human mitochondrial DNA diversity. Science. 2019; 364(6442. DOI: 10.1126/science.aau6520. View

16.

Floros V, Pyle A, Dietmann S, Wei W, Tang W, Irie N . Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nat Cell Biol. 2018; 20(2):144-151. PMC: 6551220. DOI: 10.1038/s41556-017-0017-8. View

17.

Kyriazis I, Vassi E, Alvanou M, Angelakis C, Skaperda Z, Tekos F . The impact of diet upon mitochondrial physiology (Review). Int J Mol Med. 2022; 50(5). PMC: 9542544. DOI: 10.3892/ijmm.2022.5191. View

18.

Koller A, Filosi M, Weissensteiner H, Fazzini F, Gorski M, Pattaro C . Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number. Sci Rep. 2024; 14(1):2083. PMC: 10808213. DOI: 10.1038/s41598-024-52373-0. View

19.

Ashar F, Zhang Y, Longchamps R, Lane J, Moes A, Grove M . Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. JAMA Cardiol. 2017; 2(11):1247-1255. PMC: 5710361. DOI: 10.1001/jamacardio.2017.3683. View

20.

Fazzini F, Lamina C, Raftopoulou A, Koller A, Fuchsberger C, Pattaro C . Association of mitochondrial DNA copy number with metabolic syndrome and type 2 diabetes in 14 176 individuals. J Intern Med. 2021; 290(1):190-202. PMC: 8359248. DOI: 10.1111/joim.13242. View