Sirt3 targets mPTP and prevents aging in the heart

incidence of heart failure dramatically increases with aging. An important feature of cardiac aging is an increase in susceptibility to stress, such as ischemia and hemodynamic overload [1]. The heart is an organ in which mitochondria are abundant and mitochondrial dysfunction caused by oxidative stress is believed to be an important cause of aging and failure. Mitochondrial permeability transition pore (mPTP) opening, a hallmark of mitochondrial dysfunction, causes release of pro-apoptotic factors and depletion of ATP, and eventually induces apoptosis and necrosis of cardiomyocytes depending upon the severity of ATP depletion. Elucidating the molecular mechanism by which mPTP opening is regulated during aging would provide an important clue for developing modalities to reduce the incidence of heart failure in elderly patients. In a recent publication, Hafner et al showed that Sirt3 plays an essential role in fighting against cardiac aging and increases the tolerance of the heart against hemodynamic overload [2]. Sirt3 belongs to the sirtuin family proteins, which deacetylate cellular proteins in an NAD+-dependent manner. Sirt3 is localized primarily at mitochondria and deacetylates cyclophilin D, a key component of the mPTP, thereby inhibiting mPTP opening. This in turn reduces oxidative stress and eventually slows down cardiac aging. Cardiac hypertrophy is often accompanied by oxidative stress, which causes oxidation and dysfunction of mitochondrial proteins, leading to further increases in mitochondrial oxidative stress through an amplification process called reactive oxygen species (ROS)-induced ROS release. Transition from hypertrophy to heart Regulation of the mPTP by SIRT3‐mediated deacetylation of CypD at lysine 166 suppresses age‐related cardiac hypertrophy. © Sadoshima. 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. failure is almost always accompanied by increased oxidative stress and mitochondrial dysfunction, which trigger another vicious cycle consisting of oxidative stress, mitochondrial dysfunction and cardiac hyper-trophy/dysfunction. This often makes it difficult to determine whether a given intervention acts primarily on cardiac hypertrophy, oxidative stress, or mito-chondria to improve overall cardiac function, since all are affected concomitantly. In this regard, the fact that Sirt3 localized in mitochondria directly prevents mPTP opening by modulating cyclophilin D strongly suggests that Sirt3's primary action is to suppress mPTP opening and consequent mitochondrial dysfunction, and that the suppression of cardiac hypertrophy could be secondary to the suppression of mitochondrial/cardiac dysfunction [2]. The fact that Sirt3 inhibits …