Sirtuin 3 (SIRT3) is an NAD+ dependent deacetylase that resides primarily in mitochondria and functions to maintain mitochondrial homeostasis under stress. SIRT3 expression has been observed to change under a number of different stresses in multiple tissues and model systems. Inconsistencies in the literature with regards to how and when SIRT3 protein levels change indicates that the mechanism of SIRT3 regulation is multi-faceted. Alterations in SIRT3 have been observed in experimental models of cellular stress, however, the effect these changes have on mitochondrial health remain unknown. Neurons are highly dependent on proper mitochondrial function for their survival. SIRT3 dynamics and function have been studied using models of genotoxic, metabolic, and oxidative stresses, although it remains unclear how SIRT3 is being regulated under these conditions. A closer look into SIRT3 regulation under stress conditions in various model systems will help incorporate the many SIRT3 regulatory mechanisms at play in disease states. In this review, we describe the observations that have been made about SIRT3 protein modulation under basic stress conditions. We then point out consistencies and contradictions in these observations and what they mean. Lastly, we present the observations made in the complicated neuronal stress of stroke. We hope that this review will help consolidate the ambiguous SIRT3 literature and provide a framework for investigation of SIRT3 regulation during stress response.
Longitudinal tracking is a powerful approach to understand the biology of single cells. In cancer therapy, outcome is determined at the molecular and cellular scale, yet relationships between cellular response and cell fate are often unknown. The selective inhibitor of nuclear export, selinexor, is in development for the treatment of various cancers. Selinexor covalently binds exportin-1, causing nuclear sequestration of cargo proteins, including key regulators of the cell cycle and apoptosis. The cell cycle effects of selinexor and the relationships between cell cycle effects and cell fates, has not been described for individual cells. Using fluorescent cell cycle indicators we report the majority of cell death after selinexor treatment occurs from a protracted G1-phase and early S-phase. G1- or early S-phase treated cells show the strongest response and either die or arrest, while those treated in late S- or G2-phase progress to mitosis and divide. Importantly, the progeny of cell divisions also die or arrest, mostly in the next G1-phase. Cells that survive selinexor are negative for multiple proliferation biomarkers, indicating a penetrant, arrested state. Selinexor acts quickly, shows strong cell cycle selectivity, and is highly effective at arresting cell growth and inducing death in cancer-derived cells.
Sulfotransferase 4A1 (SULT4A1), a member of cytosolic sulfotransferases (SULT), is exclusively expressed in neurons with no known function. Severe phenotype and early postnatal death in SULT4A1 knockout mice revealed that SULT4A1 is an essential neuronal protein. Localization of SULT4A1 in different cytosolic compartments, including mitochondria, suggests multiple roles for this protein. We observed that knockdown of SULT4A1 results in the accumulation of reactive oxygen species in primary cortical neurons, suggesting a potential role of SULT4A1 in regulating redox homeostasis. Expression of SULT4A1 in the human neuroblastoma SH-SY5Y cells revealed a defused but nonuniform staining pattern in the cytoplasm, with increased density around mitochondria. Subcellular fractionation of SULT4A1 expressing SH-SY5Y cells confirms the presence of SULT4A1 in mitochondrial fractions. SULT4A1 expressing cells display significant protection against H 2 O 2 -mediated defects in mitochondrial function and loss of mitochondrial membrane potential. Expression of SULT4A1 in SH-SY5Y cells also protects against H 2 O 2 -induced cell death. These data indicate that SULT4A1 protects mitochondria against oxidative damage and may serve as a potential pharmacological target in neural diseases involving mitochondrial dysfunction and oxidative stress. SIGNIFICANCE STATEMENTStudies on SULT4A1 knockout mice suggest that SULT4A1 plays a vital role in neuronal function and survival via yet undefined mechanisms. Our data demonstrate that depletion of SULT4A1 induces oxidative stress in neurons and expression of SULT4A1 in SH-SY5Y cells protects against oxidative-stress-induced mitochondrial dysfunction and cell death. These results suggest that SULT4A1 may have a crucial protective function against mitochondrial dysfunction and oxidative stress, and may serve a potential therapeutic target in different neurological diseases involving mitochondrial dysfunction and oxidative stress.
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