AKAP1 orchestrates mitochondrial dynamics and metabolic reprogramming to promote hypoxia tolerance in yak cardiac fibroblasts.

Abstract

High-altitude hypoxia poses a sustained energetic and oxidative challenge to the heart, often leading to mitochondrial dysfunction and metabolic inflexibility in nonadapted mammals. Yaks (Bos grunniens) exhibit remarkable cardiac tolerance to chronic hypoxia; however, the underlying intracellular mechanisms remain poorly defined. Herein, we identify A-kinase anchoring protein 1 (AKAP1) as an important regulator of hypoxia tolerance in yak cardiac fibroblasts. Through the genetic manipulation of AKAP1 combined with live-cell mitochondrial imaging, functional assays, and untargeted metabolomics, we demonstrate that AKAP1 confers a robust survival advantage under hypoxic stress. AKAP1 preserves mitochondrial membrane potential, maintains ATP production, limits reactive oxygen species accumulation, and sustains cell viability. Mechanistically, AKAP1 stabilizes mitochondrial network integrity by restoring the balance between fission and fusion, particularly by suppressing excessive fission. At the metabolic level, AKAP1 orchestrates cellular metabolic reprogramming, modulates lipid metabolism, maintains energetic flexibility, and regulates cAMP associated pathways. These findings provide new insights into the molecular mechanisms underlying hypoxic stress tolerance in yaks and highlight the potential role of AKAP1 in maintaining mitochondrial homeostasis and metabolic flexibility under oxygen-limited conditions.