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SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK.

ABSTRACT: Efficient coupling of cellular energy production to metabolic demand is crucial to maintain organismal homeostasis. Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis. We find that Sirt4 affects mitochondrial uncoupling via the adenine nucleotide translocator 2 (ANT2). Loss of Sirt4 expression leads to decreased cellular ATP levelsin vitro and in vivo while Sirt4 overexpression is associated with increased ATP levels. Further, we provide evidence that lack of Sirt4 activates a retrograde signaling response from the mitochondria to the nucleus that includes AMPK, PGC1?, key regulators of ?-oxidation such as Acetyl-CoA carboxylase, and components of the mitochondrial respiratory machinery. This study highlights the ability of Sirt4 to regulate ATP levels via ANT2 and a feedback loop involving AMPK.

SUBMITTER: Ho L

PROVIDER: S-EPMC3868726 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK.

Ho Linh L Titus Allen Sam AS Banerjee Kushal Kr KK George Suji S Lin Wei W Deota Shaunak S Saha Asish K AK Nakamura Ken K Gut Philipp P Verdin Eric E Kolthur-Seetharam Ullas U

Aging 20131101 11

Efficient coupling of cellular energy production to metabolic demand is crucial to maintain organismal homeostasis. Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis. We find that Sirt4 affects mitochondrial uncoupling via the adenine nucleotide translocator 2 (ANT2). Loss of Sirt4 expression leads to decreased cellular ATP levelsin vitro and in vivo while Sirt4 overexpression is associated with increased ATP levels. Further, we provide evidence that la ...[more]

PMID: 24296486

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