Inter-Organelle Crosstalk in Oxidative Distress: A Unified TRPM2-NOX2 Mediated Vicious Cycle Involving Ca<sup>2+</sup>, Zn<sup>2+</sup>, and ROS Amplification
Reactive oxygen species (ROS) are critical signalling molecules, but their overproduction leads to oxidative stress (OS), a common denominator in the pathogenesis of numerous non-communicable diseases (NCDs) and aging. General antioxidant therapies have largely been unsuccessful, highlighting the ne...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/14/7/776 |
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| Summary: | Reactive oxygen species (ROS) are critical signalling molecules, but their overproduction leads to oxidative stress (OS), a common denominator in the pathogenesis of numerous non-communicable diseases (NCDs) and aging. General antioxidant therapies have largely been unsuccessful, highlighting the need for a deeper understanding of ROS amplification mechanisms to develop targeted interventions. This review proposes a unified, self-amplifying “vicious cycle” of inter-organelle crosstalk that drives pathological ROS elevation and cellular damage. We outline a pathway initiated by extracellular stressors that co-activate plasma membrane TRPM2 channels and NADPH oxidase-2. This synergy elevates cytoplasmic Ca<sup>2+</sup>, leading to lysosomal dysfunction and permeabilization, which in turn releases sequestered Zn<sup>2+</sup>. Mitochondrial uptake of this labile Zn<sup>2+</sup> impairs electron transport chain function, particularly at Complex III, resulting in mitochondrial fragmentation, loss of membrane potential and a burst of mitochondrial ROS (mtROS). These mtROS diffuse to the nucleus, activating PARP-1 and generating ADPR, which further stimulates TRPM2, thereby perpetuating the cycle. This “circular domino effect” integrates signals generated across the plasma membrane (Ca<sup>2+</sup>), lysosomes (Zn<sup>2+</sup>), mitochondria (ROS) and nucleus (ADPR), leading to progressive organelle failure, cellular dysfunction, and ultimately cell death. Understanding and targeting specific nodes within this TRPM2-NOX2-Ca<sup>2+</sup>-Zn<sup>2+</sup>-mtROS-ADPR axis offers novel therapeutic avenues for NCDs by selectively disrupting pathological ROS amplification while preserving essential physiological redox signalling. |
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| ISSN: | 2076-3921 |