Metabolic Interventions to Treat Mitochondrial Cardiomyopathy: Roles of NAD + and Protein Acetylation in Leigh Syndrome

Leigh syndrome (LS) is a congenital neurometabolic disorder that is caused by defective mitochondrial function. LS patients also develop non‐neurological abnormalities such as cardiomyopathy and show early death in childhood. Unfortunately, LS currently has no cure and effective treatment; therefore, there is a clear need for innovation in mitochondrial medicine to treat the cardiac and neurological impairments. A mouse model of LS with deficiency of a mitochondrial Complex I subunit, Ndufs4‐null mice (KO), was previously created and allows mechanistic analyses and intervention testing. KO mice well‐recapitulate the neurological phenotypes observed in LS patients. In brain tissues from KO mice, we observed depletion of NAD + level and protein hyperacetylation, associated with elevated serum and tissue lactate levels. We and others have demonstrated the roles of NAD + depletion and protein hyperacetylation for the therapeutic benefits to treat heart failure or aging. Therefore, we hypothesized that elevation of NAD + levels will benefit KO mice. Supplementation of nicotinamide mononucleotide (NMN), a NAD + precursor, doubled the shortened lifespan of KO mice to 110 days (median lifespan of KO mice with vehicle is 55 days). However, NMN did not improve neurological impairments in KO mice, due to the failure to elevate NAD + levels in brain. Next, we determined the underlying mechanisms by which elevation of NAD + levels extended the shortened lifespan of KO mice. NMN elevated NAD + levels in skeletal and cardiac muscles of KO mice, resulting in blunted protein hyperacetylation and attenuated systolic dysfunction at 50‐day of age. NMN lowered serum and tissue lactate levels in KO mice, suggesting that elevation of NAD + levels in peripheral tissues contributes to the metabolic and cardiac improvements, and the lifespan extension. HIF1a protein and glycolytic enzymes were up‐regulated in KO mice. Activation of HIF signaling was reversed in muscles by NMN, implicating a NAD + ‐sensitive mechanism that regulates HIF‐dependent glycolytic pathway in KO mice. Acetylation did not directly regulate HIF1a stability, as HIF1a acetylation levels did not change. a‐ketoglutarate (a‐KG), a co‐substrate needed for HIF1a degradation, was up‐regulated by NMN in KO mice. Acetylation of glutamate dehydrogenase (GDH), the enzyme regulating a‐KG levels, was upregulated in KO muscle and suppressed by NMN treatment. The results suggested that GDH deacetylation promoted by NMN elevated a‐KG levels and may suppress activation of HIF signaling in KO mice. To determine the therapeutic roles of a‐KG, dimethyl‐ketoglutarate (DMKG), a cell permeable form of a‐KG, was administered to KO mice. DMKG extended lifespan and improved systolic function in KO mice, associated with suppressed HIF signaling. In summary, we identified two metabolic interventions that can benefit LS patients by relieving mitochondrial cardiomyopathy. Exploring mechanisms by which NAD + biology and protein acetylation regulate mitochondrial diseases may yield novel therapeutic targets. Support or Funding Information Scientist development grant from the American Heart Association, 17SDG33330003 to CFL and NIH R01, HL‐110349, to RT This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .