Mouse models of mitochondrial complex I dysfunction.
Diseases of the mitochondria generally affect cells with high-energy demand, and appear to most profoundly affect excitatory cells that have localized high energy requirements, such as neurons and cardiac and skeletal muscle cells. Complex I of the mammalian mitochondrial respiratory chain is a very large, 45 subunit enzyme, and functional deficiency of complex I is the most frequently observed cause of oxidative phosphorylation (OXPHOS) disorders. Impairment of complex I results in decreased cellular energy production and is responsible for a variety of human encephalopathies, myopathies and cardiomyopathies. Complex I deficiency may be caused by mutations in any of the seven mitochondrial or 38 nuclear genes that encode complex I subunits or by mutations in various other nuclear genes that affect complex I assembly or function. Mouse models that faithfully mimic human complex I disorders are needed to better understand the role of complex I in health and disease and for evaluation of potential therapies for mitochondrial diseases. In this review we discuss existing mouse models of mitochondrial complex I dysfunction, focusing on those with similarities to human mitochondrial disorders. We also discuss some of the noteworthy murine genetic models in which complex I genes are not disrupted, but complex I dysfunction is observed, along with some of the more popular chemical compounds that inhibit complex I function and are useful for modeling complex I deficiency in mice. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
Department of Pathobiology, Auburn University College of Veterinary Medicine, Auburn, AL, USA. mhi0001@auburn.edu
Michael H
MH
Irwin
Kodeeswaran
K
Parameshwaran
Carl A
CA
Pinkert
D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism*; D010085:Oxidative Phosphorylation
D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I