Abstract
Numerous mitochondrial DNA mutations cause mitochondrial encephalomyopathy: a collection of related diseases for which there exists no effective treatment. Mitochondrial encephalomyopathies are complex multisystem diseases that exhibit a relentless progression of severity, making them both difficult to treat and study. The pathogenic and compensatory metabolic changes that are associated with chronic mitochondrial dysfunction are not well understood. The Drosophila ATP61 mutant models human mitochondrial encephalomyopathy and allows the study of metabolic changes and compensation that occur throughout the lifetime of an affected animal. ATP61animals have a nearly complete loss of ATP synthase activity and an acute bioenergetic deficit when they are asymptomatic, but surprisingly we discovered no chronic bioenergetic deficit in these animals during their symptomatic period. Our data demonstrate dynamic metabolic compensatory mechanisms that sustain normal energy availability and activity despite chronic mitochondrial complex V dysfunction resulting from an endogenous mutation in the mitochondrial DNA. ATP61animals compensate for their loss of oxidative phosphorylation through increases in glycolytic flux, ketogenesis and Kreb's cycle activity early during pathogenesis. However, succinate dehydrogenase activity is reduced and mitochondrial supercomplex formation is severely disrupted contributing to the pathogenesis seen in ATP61 animals. These studies demonstrate the dynamic nature of metabolic compensatory mechanisms and emphasize the need for time course studies in tractable animal systems to elucidate disease pathogenesis and novel therapeutic avenues.
Highlights
Normal metabolic pathways in animals have been elucidated and extensively studied for decades; the response of each pathway to the loss or disturbance of another is poorly understood
Mitochondrial dysfunction results directly from mutations in the proteins involved in mitochondrial function, such as components required for oxidative phosphorylation (OXPHOS), as is the case for archetypal mitochondrial diseases
Numerous other common disorders such as Alzheimer’s disease, diabetes, cardiovascular disease, obesity and premature aging have been associated with mitochondrial dysfunction [34,35,36,37,38,39,40,41]
Summary
Normal metabolic pathways in animals have been elucidated and extensively studied for decades; the response of each pathway to the loss or disturbance of another is poorly understood. There are many human diseases that disrupt, typically via genetic hypomorphic mutations, one of these pathways Such heritable diseases known collectively as inborn errors of metabolism do not immediately cause death; they do, lead to poorly understood diseases including enzymopathies and mitochondrial encephalomyopathies. Our current understanding of mitochondrial disease has been facilitated by the study of cellular cybrids bearing human disease mutations Such systems have not yielded a clear picture of the bioenergetics and compensatory mechanisms that exist within the tissues of an intact animal with mitochondrial disease. No comprehensible understanding of the associated pathogenesis has resulted, demonstrating the inherent difficulty in using cellular models to study multisystem diseases [2,3] These diseases typically exhibit an asymptomatic period varying from days to decades, onset, and a stereotyped progression of the disease making them difficult to model in cellular systems. It is essential to study the progressive nature and tissue-specific attributes of these diseases with the goal of identifying endogenous compensatory mechanisms that might be exploited as therapeutic avenues
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