Research Paper Volume 5, Issue 11 pp 835—849
SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK
- 1 The Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA
- 2 Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai, India
- 3 The Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
- 4 Boston University, Boston, MA 02118, USA
- 5 Department of Neurology, University of California, San Francisco, CA 94158, USA
- 6 Department of Medicine, University of California, San Francisco, CA 94158, USA
Received: November 6, 2013 Accepted: November 24, 2013 Published: November 26, 2013
https://doi.org/10.18632/aging.100616How to Cite
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 levels in 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, PGC1α, key regulators of β-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.