Toward a new STATe: the role of STATs in mitochondrial function

Abstract

Signal Transducers and Activators of Transcription (STATs) have been studied extensively and have been associated with virtually every biochemical pathway. Until recently, however, they were thought to exert these effects solely as a nuclear transcription factor. The finding that STAT3 localizes to the mitochondria and modulates respiration has opened up a new avenue through which STATs may regulate the cell. Recently, other members of the STAT family (STAT1, STAT2, STAT5, and STAT6) have also been shown to be present in the mitochondria. Coordinate regulation at the nucleus and mitochondria by these proteins places them in a unique position to drive cellular processes to achieve a specific response. This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease.

Keywords: Cancer; Ischemia/reperfusion; Metabolism; Mitochondria; Review; STAT3; STATs.

Fig. 1

Model of STAT3’s mitochondrial action. Upstream activation by cytokines, growth factors, or oxidative stress likely post-translationally modifies STAT3 to target it to the mitochondria. Though still unknown, mitochondrial import of STAT3 may rely on translocases of the outer membrane (TOM20 potentially) and GRIM-19 in the inner mitochondrial membrane. Once imported, STAT3 modulates both the electron transport chain (ETC) and the mitochondrial permeability transition pore (MPTP) to regulate mitochondrial membrane potential (ΔΨ), ATP production, ROS production, and cell death. OMM: outer mitochondrial membrane; IMM: inner mitochondrial membrane.