Speaker
Description
Peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) and dominant optic atrophy (ADOA), are frequently associated with mitochondrial dysfunction. Through transcriptomic analysis, we identified the mTOR/AKT axis as a key regulator of mitochondrial homeostasis and quality control. We investigated fibroblast lines derived from three patients: two carrying mutations in mitochondrial fusion proteins MFN2 (CMT2A2) and OPA1 (ADOA), and one with a mutation in the non-mitochondrial protein MTMR5/SBF1 (CMT4B3). Our study assessed mitochondrial function, autophagy/mitophagy processes, and their impact on cellular proliferation and senescence. All patient-derived fibroblasts exhibited mitochondrial dysfunction, with MFN2 and OPA1 mutations impairing autophagosome formation but exerting divergent effects on proliferation: CMT2A2 cells displayed enhanced growth, while ADOA cells underwent premature senescence. Crucially, inhibition of the mTOR/AKT pathway restored autophagy and normalized proliferation and senescence in both conditions. These findings underscore the significance of mTOR/AKT dysregulation as a common pathological mechanism in mitochondrial-related neuropathies. Further insights into the role of CMT4B3 in mitochondrial quality control will be discussed. Our results pave the way for targeted therapeutic strategies aimed at restoring cellular homeostasis by modulating mTOR/AKT signaling in peripheral neuropathies.
| Author(s) | *Zanfardino Paola 1, Amati Alessandro 1, Sharon Cox 2, Santorelli Filippo M. 3, Petruzzella Vittoria 1 |
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| Affiliation(s) | 1 Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, 70124 Bari, Italy, 2 Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70125 Bari, Italy, 3 Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy |
