Redox modification of proteins as essential mediators of CNS autophagy and mitophagy

Abstract

Production of cellular reactive oxygen species (ROS) is typically associated with protein and DNA damage, toxicity, and death. However, ROS are also essential regulators of signaling and work in concert with redox-sensitive proteins to regulate cell homeostasis during stress. In this review, we focus on the redox regulation of mitophagy, a process that contributes to energetic tone as well as mitochondrial form and function. Mitophagy has been increasingly implicated in diseases including Parkinson's, Amyotrophic Lateral Sclerosis, and cancer. Although these disease states employ different genetic mutations, they share the common factors of redox dysregulation and autophagic signaling. This review highlights key redox sensitive signaling molecules which can enhance neuronal survival by promoting temporally and spatially controlled autophagic signaling and mitophagy.

Keywords: Amyotrophic lateral sclerosis; Atg; Energetics; FOXO; HIF; Isocitrate dehydrogenase; Mitochondria; Mitophagy; Neurodegeneration; Parkinson’s disease; Reactive oxygen species; Sirtuin; p66shc.

Fig. 1

Oxidation of PTEN promotes autophagic and mitophagic signaling. ROS reversibly oxidize PTEN allowing for prolonged PI3K/Akt signaling in response to growth factor receptor stimulation. Downstream targets of Akt stimulation include pro-survival transcription factors, such as FoxO1 and FoxO3. Transport of FoxO1 out of the nucleus initiates autophagosome formation by Atg recruitment. FoxO3 is known to target pro-autophagic genes promoting autophagosome formation.

Fig. 2

ROS inhibit PHD activity to promote autophagy and mitophagy via HIF-regulated transcription. Hypoxia and reperfusion increase production of ROS by perturbing oxidative phosphorylation. ROS inhibit the HIF1α degrading PHD complex, increasing expression of cytosolic HIF1α. HIF1α relocalizes to the nucleus when associated with HIF1β, targeting pro-survival genes, including BNIP3 and BNIP3L as well as pro-death molecules based on the extent and duration of oxygen deprivation. When BNIP3L is synthesized, it associates with mitochondria complexes with Bcl2 in competition with Beclin1. The liberation of Beclin1 promotes autophagosome formation.