TORC2 and MAPK signaling pathways regulate mitochondrial degradation induced by iron starvation in Schizosaccharomyces pombe

Abstract

Iron is essential for life as it participates in metabolic processes, including DNA synthesis, respiration, and photosynthesis. In this study, we show that iron starvation induced by 2,2'-dithiodipyl (DIP) causes mitochondrial dysfunction, impairs mitochondrial function, including mitochondrial membrane potential (ΔΨ_m) and respiration, and induces mitochondrial degradation in the vacuole of Schizosaccharomyces pombe. The DIP-induced mitochondrial degradation is independent of components of the core autophagy machinery and the ESCRT machinery examined here. We demonstrate that the target of rapamycin complex 2 (TORC2) and its sole target, the AGC kinase Gad8, and the mitogen-activated protein kinase (MAPK) Sty1 play positive roles in regulating iron starvation-induced mitochondrial degradation. The reduction in the level of mitochondrial degradation in Δgad8 cells could be restored to wild-type-like levels by treating Δgad8 cells with chloramphenicol (CAP) and NaN₃, two inhibitors of mitochondrial respiration, and by deleting genes encoding components important for mitochondrial electron transport chain (ETC). Disruption of Ca²⁺ signaling through deletion of genes encoding the Ca²⁺ channel proteins Yam8 and Cch1 and the regulatory subunit of calcineurin Cnb1 also restored mitochondrial degradation in Δgad8 cells. Our results suggest that the Sty1 MAPK participates with TORC2-Gad8 signaling in regulating DIP-induced mitochondrial degradation. Our results also suggest that TORC2-Gad8 signaling regulates iron starvation-induced mitochondrial degradation through regulation of mitochondrial respiration and Ca²⁺ signaling.

Keywords: Sty1; TORC2; calcineurin; mitochondrial degradation; respiration.