International journal of biological macromoleculesOct 25, 2025

Lactate and HIF-1a help trigger PINK1-related removal of damaged mitochondria to protect pig ovarian cells from low oxygen stress

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Lactate supplementation restores mitochondrial integrity and granulosa cell viability under hypoxic conditions.

Ovarian follicular development under chronic hypoxia leads to significant stress on granulosa cells, causing hypoxia-induced apoptosis and impaired fertility.
Lactate, traditionally viewed as a byproduct of metabolism, may play a crucial role in helping granulosa cells resist hypoxic apoptosis.
Depleting lactate aggravates mitochondrial dysfunction and apoptosis in porcine granulosa cells under hypoxia.
Supplementing with lactate stabilizes HIF-1α and enhances mitophagy, which is essential for cell survival under hypoxic stress.
In murine granulosa cells, lactate depletion also impairs mitochondrial function and increases follicular apoptosis, while lactate supplementation helps restore cell viability.
A novel signaling axis involving lactate, HIF-1α, and PINK1 is associated with granulosa cell resilience to hypoxic stress.

Simplified

Ovarian follicular development occurs under chronic hypoxia, imposing significant stress on granulosa cells (GCs) and leading to hypoxia-induced apoptosis, a key factor in follicular atresia and impaired fertility. However, the intrinsic mechanisms enabling GCs to resist hypoxic apoptosis remain unclear. Emerging evidence suggests lactate, beyond its traditional role as a glycolytic byproduct, functions as a critical mediator of cellular stress adaptation. Here, we investigated whether lactate confers protection to porcine granulosa cells (pGCs) by activating mitophagy under hypoxic conditions and elucidated the underlying molecular pathways. Using pGCs subjected to normoxia and hypoxia, combined with pharmacological inhibitors, RNA interference targeting LDHA, HIF-1α, and PINK1, mitochondrial membrane potential assays, apoptosis detection, Western blotting, and mitochondrial-lysosomal co-localization imaging, we demonstrated that lactate depletion exacerbates mitochondrial dysfunction and apoptosis under hypoxia. Conversely, exogenous lactate supplementation attenuated these effects by stabilizing HIF-1α and enhancing PINK1-Parkin-mediated mitophagy. Inhibition of mitophagy via 3-MA or PINK1 knockdown abolished lactate's protective effects, highlighting mitophagy as essential for lactate-mediated cell survival. Cross-species validation in murine granulosa cells (mGCs) in vitro and in vivo confirmed the conservation of lactate's protective mechanisms, where lactate depletion impaired mitochondrial function and increased follicular apoptosis, while lactate supplementation restored mitochondrial integrity and granulosa cell viability. Our findings reveal a novel lactate-HIF-1α-PINK1 signaling axis critical for pGCs resilience to hypoxic stress, offering new therapeutic targets for ovarian disorders such as polycystic ovary syndrome and ovarian aging.

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Competing interests

Declaration of competing interest The authors declare no competing interests.

PubMed

Lactate and HIF-1a help trigger PINK1-related removal of damaged mitochondria to protect pig ovarian cells from low oxygen stress

Abstract

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Funding

Competing interests

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