Abstract
Mitochondrial dysfunction is commonly observed in degenerative disorders, including Alzheimer's and Parkinson's disease that are characterized by the progressive and selective loss of neuronal subpopulations. It is currently unclear, however, whether mitochondrial dysfunction is primary or secondary to other pathogenic processes that eventually lead to age-related neurodegeneration. Here we establish an in vivo Drosophila model of mitochondrial dysfunction by downregulating the catalytic subunit of mitochondrial DNA (mtDNA) polymerase in cholinergic, serotonergic and dopaminergic neurons. The resulting flies are characterized by lowered respiratory chain activity, premature aging, age-related motor deficits as well as adult onset, progressive and cell-type-specific, dopaminergic neurodegeneration. Using this model, we find that associated lethality can be partially rescued by targeting PINK1/parkin signaling or Drp1, both of which have been implicated in mitochondrial dynamics and Parkinson's disease. Bypassing mitochondrial complex III/IV deficiencies with Alternative oxidase (AOX), however, fully restores ATP levels and prevents dopaminergic neurodegeneration. In contrast, ATP levels and neurodegeneration are not rescued when mitochondrial complex I deficiencies are bypassed with NADH-Q oxidoreductase. Our results demonstrate that mtDNA-mediated mitochondrial dysfunction can cause age-related and cell-type-specific neurodegeneration which AOX is able to alleviate and indicate that AOX or its surrogates may prove useful as a therapeutic tool for limiting respiratory chain deficiencies caused by mtDNA decline in healthy aging and neurodegenerative disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Aging / genetics
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Animals
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Blotting, Western
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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DNA, Mitochondrial / genetics
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DNA, Mitochondrial / metabolism
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DNA-Directed DNA Polymerase / genetics
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DNA-Directed DNA Polymerase / metabolism
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Dopaminergic Neurons / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism*
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Electron Transport / genetics
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Electron Transport Complex I / deficiency
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Electron Transport Complex I / genetics
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Electron Transport Complex I / metabolism
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism
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Humans
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondrial Diseases / genetics
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Mitochondrial Diseases / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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NADH, NADPH Oxidoreductases / genetics
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NADH, NADPH Oxidoreductases / metabolism
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism
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Oxidoreductases / genetics
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Oxidoreductases / metabolism*
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Plant Proteins / genetics
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Plant Proteins / metabolism*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Cytoskeletal Proteins
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DNA, Mitochondrial
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Drosophila Proteins
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Mitochondrial Proteins
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Plant Proteins
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Adenosine Triphosphate
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Oxidoreductases
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alternative oxidase
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NADH, NADPH Oxidoreductases
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Ubiquitin-Protein Ligases
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DNA-Directed DNA Polymerase
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DRP1 protein, Drosophila
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GTP-Binding Proteins
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park protein, Drosophila
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Electron Transport Complex I
Supplementary concepts
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Mitochondrial complex I deficiency