The malate–aspartate NADH shuttle

The malate–aspartate NADH shuttle

Recent studies suggest that increased mitochondrial metabolism and the concomitant decrease in NADH
levels mediate calorie restriction (CR)-induced life span extension. The mitochondrial inner membrane is
impermeable to NAD (nicotinamide adenine dinucleotide, oxidized form) and NADH, and it is unclear how
CR relays increased mitochondrial metabolism to multiple cellular pathways that reside in spatially distinct
compartments. Here we show that the mitochondrial components of the malate–aspartate NADH shuttle
(Mdh1 [malate dehydrogenase] and Aat1 [aspartate amino transferase]) and the glycerol-3-phosphate shuttle
(Gut2, glycerol-3-phosphate dehydrogenase) are novel longevity factors in the CR pathway in yeast.
Overexpressing Mdh1, Aat1, and Gut2 extend life span and do not synergize with CR. Mdh1 and Aat1
overexpressions require both respiration and the Sir2 family to extend life span. The mdh1aat1 double
mutation blocks CR-mediated life span extension and also prevents the characteristic decrease in the NADH
levels in the cytosolic/nuclear pool, suggesting that the malate–aspartate shuttle plays a major role in the
activation of the downstream targets of CR such as Sir2. Overexpression of the NADH shuttles may also
extend life span by increasing the metabolic fitness of the cells. Together, these data suggest that CR may
extend life span and ameliorate age-associated metabolic diseases by activating components of the NADH
shuttles…

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