Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY. Primary mitochondrial diseases (PMD) are highly morbid energy deficiency disorders with remarkably heterogeneous etiologies and phenotypes across all ages and systems, caused by pathogenic variants in > 400 different genes across both nuclear and mitochondrial genomes. No cure, FDA-approved, nor clinical trial-validated therapies exist for the indication of PMD. As one-size-fits-all, single therapy is unlikely to benefit all patients, therapeutic modeling is essential to develop precision medicines that significantly improve health in distinct molecular, biochemical, and/or clinical PMD subtypes. Specifically, pre- clinical translational RC disease investigations in human patient cells and simple animal models may efficiently identify potent therapeutic leads, and specific mechanistic targets, to meaningfully improve overall cellular and organismal health. We will exploit for this purpose our unique and growing collection of ‘matched’ nuclear gene-based PMD model sets for complex I (NDUFS2, NUBPL), complex IV (SURF1), multiple respiratory chain complexes (FBXL4, C12ORF65, MT-ARS2), and interacting pathways (DLD, OPA1) in 3 evolutionarily distinct species using C. elegans (worm, invertebrate), D. rerio (zebrafish, vertebrate), and humans (derived cell lines), as well as our newer array of heteroplasmic mtDNA mutant zebrafish and cybrid cell models. Having validated many novel, in vivo approaches to quantify PMD effects on survival and diverse cellular and animal- level functions, we are strongly situated to harness this patented, multi-species preclinical modeling approach to gain further mechanistic insights and identify promising new therapeutic leads for diverse PMD subtypes and secondary mitochondrial disorders. NIGMS R35 MIRA support will enable this basic and translational research program, built over the past 18 years by an established physician-scientist research investigator who has been highly productive and provided many teaching opportunities, to continue to advance the scientific evidence base for precision mitochondrial medicine. Specifically, this translational research program will focus on harnessing PMD cells and simple animal models to investigate key questions across 2 overarching themes. Theme 1 is ‘Pathophysiology Investigations in PMD cell and animal models’, involving 2 project areas: (i) Understanding the mechanistic basis by which distinct organ pathophysiology and metabolic dysfunction predominates in different forms of PMD; and (ii) Determining which central nutrient-sensing signaling network node(s) and downstream biochemical pathways that regulate cellular proteotoxic stress underlie candidate therapies response in specific PMD subsets. Theme 2 is ‘Preclinical therapeutic discovery in PMD cell and animal models’, involving 2 project areas: (iii) Therapeutic target and compound discovery and validation in distinct PMD animal and cell translational disease variant models; and (iv) Identify whether treatments that improve health in genetic-based PMD will improve health in complex disorders with secondary forms of mitochondrial dysfunction that are chronic (eg, Down or Cockayne syndrome) or acute (toxin-induced).