SIRT3-mediated mitochondrial reprogramming: Emerging therapeutic paradigms in peripheral neuropathy and neuropathic pain.

Peripheral neuropathy is a debilitating condition resulting from peripheral nerve damage or dysfunction, primarily caused by aging, obesity, diabetes, cancer chemotherapy, HIV infection, ischemia, or trauma. It manifests as sensory, motor, and autonomic impairments, with symptoms such as numbness, tingling, weakness, and pain, most commonly affecting the hands and feet. Among these, neuropathic pain is the most debilitating, often worsening at night and contributing to insomnia, mood disturbances, depression, and reduced quality of life. Mitochondrial dysfunction is a key pathological hallmark in the onset and progression of peripheral neuropathy and neuropathic pain. Sirtuin 3 (SIRT3), a NAD+-dependent mitochondrial deacetylase, plays a crucial role in maintaining mitochondrial homeostasis by deacetylating >250 lysine residues across ∼115 mitochondrial proteins. Through this mechanism, SIRT3 regulates mitochondrial energy metabolism, oxidative phosphorylation, calcium buffering, redox balance, membrane integrity, DNA repair, proteostasis, biogenesis, dynamics, mitophagy, and autophagy. Emerging evidence suggests that reduced SIRT3 expression and activity contribute to mitochondrial dysfunction associated with peripheral neuropathy and neuropathic pain. Conversely, its restoration has been shown to improve mitochondrial health, suppress nitro-oxidative and inflammatory nerve damage, and alleviate neuropathic symptoms. This review critically examines the role of mitochondrial dysfunction in the pathogenesis of peripheral neuropathy and neuropathic pain. Furthermore, we summarize recent advances in SIRT3 biology, regulation, and acetylproteome, highlighting their implications for mitochondrial function and neuroprotection. Lastly, we provide a comprehensive analysis of literature supporting SIRT3 as a promising therapeutic target, discussing strategies to enhance its expression or activity through lifestyle modifications, natural compounds, small molecules, and genetic approaches. These insights may pave the way for novel therapeutic interventions in peripheral neuropathy and neuropathic pain.