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.

Effects of multiple stressors on pancreatic human islets proteome reveal new insights into the pathways involved

“…In the present study, 16 proteins were involved in peroxisomal protein import pathway with consistently increased expression levels in cytokine‐treated group (Figure 2B(ii)); of which peroxisomal biogenesis factor 3 (PEX3) and peroxisomal membrane protein (PEX14) are essential components of the peroxisomal import machinery. An immunohistochemistry study on mouse model demonstrated that PEX14 immunoreactivity was significantly higher in the endocrine compared to exocrine pancreas [32, 33]. In line with this observation, a recent study has also reported PEX14 to express and participate in the regulation of immune signaling responses [35].…”

“…Peroxisomes are membrane-bound organelles involved in multiple pathways and play an important role in lipid and ROS metabolism and anti-inflammatory responses [32,33]. The Peroxisome Proliferator-Activated Receptor (PPAR) family proteins modulate glucose stimulated insulin secretion in pancreatic β-cells [34], and normal peroxisome metabolism is crucial to preserve the structure and function of β-cells in mice [32].…”

The physiological functions of human peroxisomes

“…The ROS (over)production promotes PEX5-mediated targeting of the 'ataxia-telangiectasia mutated' (ATM) kinase to peroxisomes during or after which the ATM kinase phosphorylates PEX5 which promotes ubiquitination of PEX5 by the PEX2-PEX10-PEX12 complex. The ubiquitinated PEX5 is then recognized by the autophagy adapter protein SQSTM1/P62 which targets the peroxisome to the autophagy machinery eventually resulting in its degradation (238,239). Pexophagy can also be induced by amino acid starvation, which results in ubiquitination of PEX5 and the peroxisomal membrane protein ABCD3, and possibly additional peroxisomal membrane proteins, by PEX2, targeting the peroxisome for degradation (240).…”

Sharing the wealth: The versatility of proteins targeted to peroxisomes and other organelles

“…Regulation of dual targeting via metabolites such as H 2 O 2 is likely to operate in plants similar to what was observed in mammals ( Okumoto et al, 2020 ). Peroxisomes together with mitochondria have a key role in controlling ROS production, which is important for cellular signaling and needs to be maintained on a level acceptable for the integrity of cells, especially of the nucleus ( Fransen et al, 2017 ; Sies, 2017 ; Li et al, 2021 ; Paradis et al, 2021 ).…”