Research Paper|Volume 5, Issue 11|pp 835—849

SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK

Linh Ho¹, Allen Sam Titus², Kushal Kr Banerjee², Suji George², Wei Lin³, Shaunak Deota², Asish K. Saha⁴, Ken Nakamura^3,⁵, Philipp Gut¹, Eric Verdin^1,⁶, Ullas Kolthur-Seetharam²

¹The Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA
²Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai, India
³The Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
⁴Boston University, Boston, MA 02118, USA
⁵Department of Neurology, University of California, San Francisco, CA 94158, USA
⁶Department of Medicine, University of California, San Francisco, CA 94158, USA

* * Equal contribution

Received: November 6, 2013Accepted: November 24, 2013Published: November 26, 2013

https://doi.org/10.18632/aging.100616

Copyright: © 2013 Ho et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.