The pathophysiology of mitochondrial disease as modeled in the mouse

Abstract

It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria's central role in energy production, reactive oxygen species (ROS) biology, and apoptosis, and because the mitochondrial genome consists of roughly 1500 genes distributed across the maternal mitochondrial DNA (mtDNA) and the Mendelian nuclear DNA (nDNA). While numerous pathogenic mutations in both mtDNA and nDNA mitochondrial genes have been identified in the past 21 years, the causal role of mitochondrial dysfunction in the common metabolic and degenerative diseases, cancer, and aging is still debated. However, the development of mice harboring mitochondrial gene mutations is permitting demonstration of the direct cause-and-effect relationship between mitochondrial dysfunction and disease. Mutations in nDNA-encoded mitochondrial genes involved in energy metabolism, antioxidant defenses, apoptosis via the mitochondrial permeability transition pore (mtPTP), mitochondrial fusion, and mtDNA biogenesis have already demonstrated the phenotypic importance of mitochondrial defects. These studies are being expanded by the recent development of procedures for introducing mtDNA mutations into the mouse. These studies are providing direct proof that mtDNA mutations are sufficient by themselves to generate major clinical phenotypes. As more different mtDNA types and mtDNA gene mutations are introduced into various mouse nDNA backgrounds, the potential functional role of mtDNA variation in permitting humans and mammals to adapt to different environments and in determining their predisposition to a wide array of diseases should be definitively demonstrated.

Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

“…28,29 Inoue et al 30 reported that large-scale mtDNA depletion in hematopoietic cells leads to failure in erythropoiesis and resultant macrocytic anemia, indicating that erythrocyte differentiation is susceptible to mitochondrial respiration defects. Further, Chen et al 31 reported that mtDNA polymerase γ (POLG) mutant mice developed a progressive and ultimately fatal megaloblastic anemia that was associated with both erythrodysplasia and impaired lymphopoiesis, similar to the phenotype of our Ant2-depleted mice.…”

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…Mitochondrial dysfunction, whether it is attributable to deleterious mutations in nuclear or mtDNA genes (DiMauro and Hirano 2009;Wallace and Fan 2009) or to secondary systemic changes caused by factors such as aging/senescence, significantly impairs cell function and can result in a spectrum of pathologies. In certain circumstances, such as aging, the mechanisms for why or how mitochondrial function and dynamics become abnormal are unknown (Petersen et al 2003;Reznick et al 2007).…”

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

“…Mitochondrial transcription factor A (TFAM) is encoded by nuclear DNA and regulates mitochondrial biogenesis and mitochondrial DNA (mtDNA) transcription [1,28]. The mitochondrial genome encodes some mETC complex subunits, such as ND1-6 and ND4L of complex I, Cyt b of complex III, COX I-III of complex IV, and ATPase 6 and 8 of complex V, along with mitochondrial rRNA and tRNA [29]. We first investigated whether TFAM was induced and found that it was increasingly induced during muscle differentiation ( Figure 5A).…”