Cadmium and lead induce mitochondrial dysfunction in ovarian theca Cells: Mechanisms of oxidative stress and bioenergetic collapse

Abstract

Heavy metals (HMs), particularly lead (Pb) and cadmium (Cd), are hazardous environmental toxicants with toxic effects on female reproductive health. This study investigated the impact of Pb and Cd on mitochondrial energetics in theca interstitial cells (TICs). At their respective EC₅₀ values (15 μM Pb, 5 μM Cd), both metals induced severe mitochondrial impairment, characterized by diminished ATP production and oxygen consumption rates (OCR) alongside loss of mitochondrial membrane potential (MMP). Additionally, Pb and Cd reduced mitochondrial mass, disrupted mitophagy protein expression, and inhibited activities of respiratory chain complexes, paralleled by downregulation of their subunit-coding genes. Both metals elevated lactate production, indicating a metabolic shift toward glycolysis. Structural alterations included increased mitochondrial swelling, enhanced membrane permeability to H⁺ and K⁺ ions, and elevated mitochondrial membrane fluidity (MMF) driven by a higher saturated-to-unsaturated fatty acid ratio. These effects were concentration- and time-dependent. Furthermore, Pb and Cd significantly suppressed progesterone and androstenedione secretion, underscoring endocrine disruption. Collectively, our findings demonstrate that Pb and Cd induce mitochondrial dysfunction in TICs through bioenergetic failure, structural damage, and oxidative stress, providing a mechanistic basis for HM-associated reproductive pathologies. Targeting mitochondrial integrity may offer therapeutic potential for mitigating HM-induced ovarian dysfunction in at-risk populations.