Combinatorial glucose, nicotinic acid and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease

Author:

Guha Sujay1,Mathew Neal D1,Konkwo Chigoziri1,Ostrovsky Julian1,Kwon Young Joon1,Polyak Erzsebet1,Seiler Christoph2,Bennett Michael3,Xiao Rui4,Zhang Zhe5,Nakamaru-Ogiso Eiko1,Falk Marni J16ORCID

Affiliation:

1. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

2. Aquatics Core Facility, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

3. Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

4. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

5. Center for Biomedical Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

6. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Abstract

Abstract Mitochondrial respiratory chain disorders are empirically managed with variable antioxidant, cofactor and vitamin ‘cocktails’. However, clinical trial validated and approved compounds, or doses, do not exist for any single or combinatorial mitochondrial disease therapy. Here, we sought to pre-clinically evaluate whether rationally designed mitochondrial medicine combinatorial regimens might synergistically improve survival, health and physiology in translational animal models of respiratory chain complex I disease. Having previously demonstrated that gas-1(fc21) complex I subunit ndufs2−/−  C. elegans have short lifespan that can be significantly rescued with 17 different metabolic modifiers, signaling modifiers or antioxidants, here we evaluated 11 random combinations of these three treatment classes on gas-1(fc21) lifespan. Synergistic rescue occurred only with glucose, nicotinic acid and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential that reflects integrated respiratory chain function, without exacerbating oxidative stress, and while reducing mitochondrial stress (UPRmt) and improving intermediary metabolic disruptions at the levels of the transcriptome, steady-state metabolites and intermediary metabolic flux. Equimolar Glu + NA + NAC dosing in a zebrafish vertebrate model of rotenone-based complex I inhibition synergistically rescued larval activity, brain death, lactate, ATP and glutathione levels. Overall, these data provide objective preclinical evidence in two evolutionary-divergent animal models of mitochondrial complex I disease to demonstrate that combinatorial Glu + NA + NAC therapy significantly improved animal resiliency, even in the face of stressors that cause severe metabolic deficiency, thereby preventing acute neurologic and biochemical decompensation. Clinical trials are warranted to evaluate the efficacy of this lead combinatorial therapy regimen to improve resiliency and health outcomes in human subjects with mitochondrial disease.

Funder

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics(clinical),Genetics,Molecular Biology,General Medicine

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