Hydrogen sulfide mitigates iron-induced mitochondrial dysfunction in vascular smooth muscle cells.

Mitochondrial dysfunction is a key contributor to cellular stress, impaired metabolism, and disease progression. Oxidative stress and iron overload further exacerbate mitochondrial impairment. While wild-type (WT) vascular smooth muscle cells (VSMCs) maintain redox balance under iron exposure, cystathionine γ-lyase knockout (CSE-KO) cells have impaired iron-regulating mechanisms, making them more susceptible to iron overload and oxidative stress. This study investigates how iron exposure affects mitochondrial respiration and whether hydrogen sulfide (H2S) can mitigate these effects. Seahorse XF96 analysis revealed that iron-treated CSE-KO cells exhibited impaired mitochondrial respiration, reduced maximal respiratory capacity, and diminished spare respiratory capacity. In contrast, WT cells maintained a higher spare respiratory capacity, suggesting a protective role of endogenous H2S. JC-1 staining confirmed that CSE-KO cells undergo mitochondrial dysfunction upon iron exposure with disrupted membrane potential. However, H2S treatment of CSE-KO cells restored mitochondrial function and prevented membrane depolarization. These findings enhance our understanding of the iron-H2S interaction in mitochondrial regulation, which can be leveraged for therapeutic strategies to enhance mitochondrial resilience and mitigate iron-induced cellular damage.