Rapamycin enhances survival in aDrosophilamodel of mitochondrial disease

Abstract

Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS. However, the mechanism by which TOR inhibition exerts these effects, and the extent to which these effects can extend to other models of mitochondrial deficiency, are unknown. Here, we probe the effects of TOR inhibition in a Drosophila model of complex I deficiency. Treatment with rapamycin robustly suppresses the lifespan defect in this model of LS, without affecting behavioral phenotypes. Interestingly, this increased lifespan in response to TOR inhibition occurs in an autophagy-independent manner. Further, we identify a fat storage defect in the ND2 mutant flies that is rescued by rapamycin, supporting a model that rapamycin exerts its effects on mitochondrial disease in these animals by altering metabolism.

Maternally inherited differences within mitochondrial Complex I control murine healthspan

“…In the present study, we presented experimental evidence that variations in mtDNA-encoded complex I genes, i.e., mt-Nd2 and mt-Nd5, differentially affected lifespan and metabolic phenotypes in mammals. Our results are in line with previously reported studies using Drosophila carrying a mutation in the ND2 gene (ND2 del1 ), i.e., shorter lifespan as well as impaired fat storage, apart from Leigh syndrome-like (or spontaneous) neurological dysfunction 19,30 . These studies suggested that ND2 mutations led to the shorter lifespan.…”

Metabolic etiologies in West syndrome

“… Ndufs4 KO mice Delayed growth, progressive lethargy, ataxia, blindness, progressive loss of startle response & death at week 7 due to systemic KO, hypoxia reversed neurodegenerative changes & ↑ life span, rapamycin also extended life span, prevented brain injury, ↑ GABA, dopamine and free fatty acid levels, ↓glycolytic intermediates Similar outcome as in the systemic knockout, in addition, gliosis & microglial activation due to KO only in glial cells and neurons ND2 deletion in Drosophila Rapamycin increases the life span but leads to fat storage impairments …”

Strategies for fighting mitochondrial diseases

“…A rather large number of studies on different in vivo and cellular models confirmed this result, including (i) a muscle‐specific Cox15 knockout mouse [24], (ii) a ND2 ‐deficient Drosophila model of LS [25], (iii) iPSCs‐derived neurons carrying a mutation in the MT‐ATP6 gene [26], (iv) the CoQ‐deficient mouse B6.Pdss2 kd/kd , (v) the gas‐1(fc21) nematodes [27], carrying a homozygous mutation in the complex I NDUFS2 subunit homologue, (vi) the Deletor mouse and (vi) the Tk2 knock‐in mouse model ( Tk2 H126N ) [28]. However, the mechanism by which rapamycin has beneficial effects in mitochondrial disease models is highly debated.…”