Ho Linh, Titus Allen Sam, Banerjee Kushal Kr, George Suji, Lin Wei, Deota Shaunak, Saha Asish K, Nakamura Ken, Gut Philipp, Verdin Eric, Kolthur-Seetharam Ullas
Aging (Albany NY). 2013 Nov;5(11):835-49. doi: 10.18632/aging.100616.
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, 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.
细胞能量产生与代谢需求的有效耦合对于维持机体稳态至关重要。在此，我们报告线粒体去乙酰化酶Sirt4调节线粒体ATP稳态。我们发现Sirt4通过腺嘌呤核苷酸转位酶2（ANT2）影响线粒体解偶联。Sirt4表达缺失导致体外和体内细胞ATP水平降低，而Sirt4过表达与ATP水平升高相关。此外，我们提供的证据表明，Sirt4的缺失激活了从线粒体到细胞核的逆行信号反应，其中包括AMPK、PGC1α、β-氧化的关键调节因子如乙酰辅酶A羧化酶以及线粒体呼吸机制的组成部分。这项研究突出了Sirt4通过ANT2和涉及AMPK的反馈回路调节ATP水平的能力。
