title: SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis.
abstract: It is a well-established scientific observation that mammalian cells contain fidelity proteins that appear to protect against and adapt to various forms of endogenous and exogenous cellular conditions. Loss of function or genetic mutation of these fidelity proteins has also been shown to create a cellular environment that is permissive for the development of tumors, suggesting that these proteins also function as tumor suppressors (TSs). While the first identified TSs were confined to either the nucleus and/or the cytoplasm, it seemed logical to hypothesize that the mitochondria may also contain fidelity proteins that serve as TSs. In this regard, it now appears clear that at least two mitochondrial sirtuins function as sensing, watchdog, or TS proteins in vitro, in vivo, and in human tumor samples. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity/sensing proteins, SIRT3 and SIRT4, respond to changes in cellular nutrient status to alter the enzymatic activity of specific downstream targets to maintain energy production that matches energy availability and ATP consumption. As such, it is proposed that loss of function or genetic deletion of these mitochondrial genes results in a mismatch of mitochondrial energy metabolism, culminating in a cell phenotype permissive for transformation and tumorigenesis. In addition, these findings clearly suggest that loss of proper mitochondrial metabolism, via loss of SIRT3 and SIRT4, is sufficient to promote carcinogenesis.
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yufan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Surgery, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA ; Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Rm 3-119, Lurie Research Bldg., 303 East Superior, Chicago, IL 60611, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gius
keywords: Acetylation; Acetylome; Carcinogenesis; SIRT3; SIRT4