Dysfunction of complex I of the mitochondrial respiratory chain (RC) commonly causes multi-systemic diseases that can manifest at any age, often involving severe neurodevelopmental impairment, developmental regression, autism-spectrum behaviors, leukoencephalopathy, basal ganglia stroke, ataxia, and seizures. Cellular mechanisms that cause disease are not known, thereby hampering effective treatment attempts. Improved understanding of the cellular pathophysiology mediating disease in genetic-based RC dysfunction may lead to novel treatment options. Our preliminary data suggests that alterations of the PPAR/SIRT1 signaling pathway occur in animal models and human patients with RC dysfunction. We hypothesize that NAD+ deficiency and/or increased oxidant stress caused by RC complex I dysfunction inhibits PPAR/SIRT1 pathway signaling, which then orchestrates downstream deleterious effects across many aspects of intermediary metabolism.
Our specific aim i s to determine whether pharmacologic modulation of the PPAR/SIRT1 pathway will attenuate, or even reverse, the metabolic sequelae of complex I dysfunction. We will pursue this goal in a C. elegans model that harbors a missense mutation in a nuclear gene encoding a subunit of RC complex I (gas-1(fc21)) through study of 5 agents that directly modulate the PPAR/SIRT1 pathway. Therapeutic effects will be assessed by analysis of (a) Lifespan (primary endpoint); (b) Global metabolomic response reflected in 3 complementary assays: i) Microarray expression analysis of biochemical pathways, ii) Stable isotopic analysis of in vivo metabolic flux;iii) Quantitative PCR analysis of PPAR/SIRT1 pathway gene expression;and (c) Integrated mitochondrial functions assessed by fluorescence microscopy of in vivo mitochondria content, membrane potential, and matrix oxidant burden. We will further investigate phenotypic responses by in vivo functional analyses in gas-1(fc21) complex 1 mutants that harbor secondary knockdown by RNA interference for individual PPAR/SIRT1 pathway genes. The C. elegans models thus allows for low-cost and rapid evaluation of novel therapeutic targets for mitochondrial RC dysfunction, a form of human neurologic disease for which effective treatment remains elusive.

Public Health Relevance

The ability to treat a devastating class of neurologic diseases that are caused by mitochondrial complex I dysfunction will be objectively studied in a simple C. elegans model animal through pharmacologic modulation of the highly conserved PPAR/SIRT1 signaling pathway that orchestrates metabolism.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Center Core Grants (P30)
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Special Emphasis Panel (ZHD1-MRG-C)
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Children's Hospital of Philadelphia
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