The Peroxisome-Autophagy Redox Connection: A Double-Edged Sword?

Abstract

Peroxisomes harbor numerous enzymes that can produce or degrade hydrogen peroxide (H₂O₂). Depending on its local concentration and environment, this oxidant can function as a redox signaling molecule or cause stochastic oxidative damage. Currently, it is well-accepted that dysfunctional peroxisomes are selectively removed by the autophagy-lysosome pathway. This process, known as "pexophagy," may serve a protective role in curbing peroxisome-derived oxidative stress. Peroxisomes also have the intrinsic ability to mediate and modulate H₂O₂-driven processes, including (selective) autophagy. However, the molecular mechanisms underlying these phenomena are multifaceted and have only recently begun to receive the attention they deserve. This review provides a comprehensive overview of what is known about the bidirectional relationship between peroxisomal H₂O₂ metabolism and (selective) autophagy. After introducing the general concepts of (selective) autophagy, we critically examine the emerging roles of H₂O₂ as one of the key modulators of the lysosome-dependent catabolic program. In addition, we explore possible relationships among peroxisome functioning, cellular H₂O₂ levels, and autophagic signaling in health and disease. Finally, we highlight the most important challenges that need to be tackled to understand how alterations in peroxisomal H₂O₂ metabolism contribute to autophagy-related disorders.

Keywords: autophagy; disease; hydrogen peroxide; oxidative damage; peroxisomes; pexophagy; thiol-based redox signaling.