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.

Keywords: Acetylation; Acetylome; Carcinogenesis; SIRT3; SIRT4.

Figure 1

Overview of sirtuin biology. (A) Cellular localization of the nuclear, cytoplasmic, and mitochondrial sirtuins. (B) Schematic of the enzymatic function of mitochondrial sirtuins using SIRT3.

Figure 2

Cancer incidence rises with age. (A) The incidence of solid tumor cancers derived from somatic cells increases exponentially with age. The circle marks the inflection point at the transition between the early (E) slope and steep (S) slope. (B) The effect of sirtuin gene expression on lifespan. This is a graphical summary of data obtained from increased or decreased sirtuin expression in C. elegans. Overexpression of sirtuin genes results in increased lifespan (curve C), whereas underexpression of these genes shortened lifespan (curve B). The time of the inflection point (circle) is shifted, but the general shape of the survival curve remains unchanged.

Figure 3

Effects of caloric restriction on murine survival and carcinogenesis. (A) Overall survival or longevity in mice on a standard ad libitum diet or CR diets consisting of 85, 50, or 40 kcal/week. The black circles highlight the inflection points of the survival curves on the ad libitum and 40 kcal/week diets. (B) The incidence of pancreatic cancers in an LSL-KrasG12D genetic knock-in mouse model on either an ad libitum diet or a CR diet. Results are presented as %survival or %tumor free, respectively, as a function of mouse age.

Figure 4

Schema outlining the opposing effects of the kinome and the acetylome on metabolism in response to energy availability. Fed conditions favor oxidative damage due to the induction of pro-metabolism pathways that are induced by insulin and other cytokines that signal a high-energy availability status that would inactivate sirtuins. A fasting state is proposed to activate sirtuins and should induce cellular pathways that conserve or increase cellular efficiency, resulting in energy conservation and preservation of cellular integrity.

Figure 5

Schema outlining the multiple mechanisms by which SIRT3 blocks ROS production, thereby preventing carcinogenesis. Loss of SIRT3 results in mitochondrial dysregulation as well as increased ROS, due in part to increased mitochondrial protein acetylation, including that in MnSOD, and decreased MnSOD detoxification activity as well as other downstream target proteins deacetylated by SIRT3. The increase in ROS is thought to be an early event in the in vivo carcinogenesis observed in mice lacking Sirt3.

Figure 6

Schema outlining the proposed pathway by which SIRT4 regulates proliferation. It is proposed that under nutrient rich conditions mTORC1 inhibits CREB2, decreasing the expression of SIRT4. When SIRT4 activity is decreased, which is observed in the Sirt4 knockout mice, and what might be expected with increasing age, the glutamate/αketoglutarate and TCA cycles are dysregulated. As such, it is suggested that this plays a role, at least in some part, in the tumor-permissive phenotype in mice lacking Sirt4.