Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies

Mar 16, 2026Translational research : the journal of laboratory and clinical medicine

New Treatment Approaches Targeting Mitochondrial Problems and Cell Death Pathways

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Abstract

Mitochondrial dysfunction is associated with the initiation of PANoptosis, a coordinated inflammatory cell death pathway.

Mitochondria play a critical role in energy production and metabolic regulation.
PANoptosis combines features of pyroptosis, apoptosis, and necroptosis, executed by multiprotein complexes called PANoptosomes.
Mitochondrial danger signals, such as reactive oxygen species and mitochondrial DNA, act as triggers for PANoptosis.
Defects in mitochondrial functions, including oxidative phosphorylation and mitophagy, may enhance inflammatory signals leading to PANoptosis.
This mitochondrial-PANoptosis axis is implicated in various diseases, suggesting potential therapeutic targets.

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Mitochondria are fundamental organelles that regulate cellular homeostasis through energy production, metabolic integration, and signaling cascades. Beyond their bioenergetic role, mitochondrial dysfunction is increasingly recognized as a pivotal instigator of PANoptosis, a novel, coordinated inflammatory cell death pathway that amalgamates key features of pyroptosis, apoptosis, and necroptosis. This integrated cell death is executed by multiprotein complexes termed PANoptosomes, which are nucleated by specific sensors like ZBP1, AIM2, and NLRC5. Central to this process is the release of mitochondrial danger signals, including reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which act as potent upstream triggers. For instance, ROS can directly oxidize and activate necroptotic mediators like RIPK1, while cytosolic mtDNA engages innate immune sensors such as cGAS-STING and inflammasomes, thereby initiating PANoptosome assembly. Concurrently, defects in core mitochondrial processes including impaired oxidative phosphorylation, disrupted dynamics (fission/fusion), and faulty mitophagy exacerbate these inflammatory signals, creating a permissive environment for PANoptosis. This mitochondrial-PANoptosis axis is implicated in the pathogenesis of a broad spectrum of diseases. Consequently, therapeutic strategies targeting mitochondrial integrity or specific PANoptotic components hold significant promise for mitigating pathological inflammation and cell loss. This review focuses on the molecular mechanisms linking mitochondrial dysfunction to PANoptosis and explores the translational potential of this interplay to reshape therapeutic approaches in diseases.

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Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies

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