Mitochondrial structure, function, and genetics
- Erin O'Ferrall, MD
Erin O'Ferrall, MD
- Assistant Professor
- McGill University
- Section Editors
- Jeremy M Shefner, MD, PhD
Jeremy M Shefner, MD, PhD
- Section Editor — Neuromuscular Disease
- Professor and Chair of Neurology, Barrow Neurological Institute
- Professor of Neurology, University of Arizona, Phoenix
- Clinical Professor of Neurology, Creighton University
- Sihoun Hahn, MD, PhD
Sihoun Hahn, MD, PhD
- Section Editor — Genetics
- Professor of Pediatrics
- University of Washington School of Medicine, Seattle Children's Hospital
Mitochondrial diseases can be defined as a group of chronic, genetically determined disorders caused by dysfunction of the mitochondria, which are organelles found in almost every cell type in the human body. Mitochondrial diseases encompass myopathies, encephalomyopathies, and multisystemic diseases that are caused by mitochondrial or nuclear DNA defects. In addition, mitochondrial dysfunction is emerging as important in the pathogenesis of a range of conditions including neurodegenerative diseases (Parkinson, Alzheimer, and Huntington diseases), cardiovascular disease, cancer, and even the aging process. This understanding has challenged the previously held view that mitochondrial diseases are limited to those affecting (directly or indirectly) the proteins of the respiratory chain.
Since 2005, there has been an enormous expansion in both the phenotypic and genotypic diversity of mitochondrial disease. There has been a parallel expansion in our knowledge of mitochondrial function. Mitochondria are no longer conceptualized as simply the "power houses" of the cell (ie, referring to the role of the mitochondrial in producing energy) but are now known to play important roles in a diverse range of cellular processes from apoptosis to immunity.
This topic will give a brief overview of mitochondrial structure, function, and genetic attributes. Clinical aspects of mitochondrial disorders are discussed separately. (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Renal involvement in the mitochondrial cytopathies".)
Mitochondria are intracellular organelles found in almost all human cells.
Mitochondria are thought to be derived from aerobic bacteria that invaded the proto eukaryotic cell more than a billion years ago and lived in a symbiotic relationship with it, exchanging energy in the form of adenosine triphosphate (ATP) for residence. However, this "endosymbiotic hypothesis" is not universally accepted and has been challenged .
- Martin W, Müller M. The hydrogen hypothesis for the first eukaryote. Nature 1998; 392:37.
- Friedman JR, Nunnari J. Mitochondrial form and function. Nature 2014; 505:335.
- DiMauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005; 15:276.
- DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol 2006; 18:636.
- Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing mitochondrial disease: What is new and what challenges remain? Science 2015; 349:1494.
- DiMauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol 2013; 9:429.
- Nardin RA, Johns DR. Mitochondrial dysfunction and neuromuscular disease. Muscle Nerve 2001; 24:170.
- Pandey A, Pain J, Ghosh AK, et al. Fe-S cluster biogenesis in isolated mammalian mitochondria: coordinated use of persulfide sulfur and iron and requirements for GTP, NADH, and ATP. J Biol Chem 2015; 290:640.
- Herrmann JM, Longen S, Weckbecker D, Depuydt M. Biogenesis of mitochondrial proteins. Adv Exp Med Biol 2012; 748:41.
- De Silva D, Tu YT, Amunts A, et al. Mitochondrial ribosome assembly in health and disease. Cell Cycle 2015; 14:2226.
- Powell CA, Nicholls TJ, Minczuk M. Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. Front Genet 2015; 6:79.
- Gao J, Wang L, Liu J, et al. Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases. Antioxidants (Basel) 2017; 6.
- Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E. The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun 2017; 482:426.
- West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol 2011; 11:389.
- Lu YW, Claypool SM. Disorders of phospholipid metabolism: an emerging class of mitochondrial disease due to defects in nuclear genes. Front Genet 2015; 6:3.
- Giorgi C, Missiroli S, Patergnani S, et al. Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid Redox Signal 2015; 22:995.
- Filadi R, Theurey P, Pizzo P. The endoplasmic reticulum-mitochondria coupling in health and disease: Molecules, functions and significance. Cell Calcium 2017; 62:1.
- Matheoud D, Sugiura A, Bellemare-Pelletier A, et al. Parkinson's Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation. Cell 2016; 166:314.
- Chinnery PF. Mitochondrial disorders overview. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1224/ (Accessed on February 21, 2017).
- Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015; 77:753.
- Area-Gomez E, Schon EA. Mitochondrial genetics and disease. J Child Neurol 2014; 29:1208.
- Wallace DC. The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene 2005; 354:169.
- MITOMAP: A human mitochondrial genome database. http://mitomap.org/MITOMAP (Accessed on February 21, 2017).
- Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial disorders. N Engl J Med 2012; 366:1132.
- Schwartz M, Vissing J. New patterns of inheritance in mitochondrial disease. Biochem Biophys Res Commun 2003; 310:247.
- Sutovsky P, Moreno RD, Ramalho-Santos J, et al. Ubiquitin tag for sperm mitochondria. Nature 1999; 402:371.
- Kvist L, Martens J, Nazarenko AA, Orell M. Paternal leakage of mitochondrial DNA in the great tit (Parus major). Mol Biol Evol 2003; 20:243.
- Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347:576.
- Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet 2005; 6:389.
- McFarland R, Clark KM, Morris AA, et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet 2002; 30:145.
- Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 1998; 121 ( Pt 10):1889.
- Energy production and metabolism
- Respiratory chain
- Mitochondrial DNA replication, maintenance, and transcription
- Mitochondrial protein synthesis
- Mitochondrial dynamics
- Production of reactive oxygen species
- Calcium homeostasis
- Maintenance of the lipid membrane
- MITOCHONDRIAL GENETICS
- Mitochondrial DNA
- - Mutation rate
- - Maternal inheritance
- - Heteroplasmy
- - Threshold effect
- - Mitotic segregation
- - Postmitotic replication
- Nuclear DNA