Mitochondrial homeostasis: the central hub governing the progression of atherosclerosis.

Atherosclerosis is a disease centered on chronic inflammation, in which mitochondrial damage plays a key role in its initiation and progression. Traditionally, atherosclerosis is thought to be triggered by cholesterol accumulation, but recent studies have revealed that mitochondrial dysfunction has emerged as an important driving factor by inducing innate immune imbalance. In atherosclerosis, mitochondria undergo changes in membrane permeability, metabolic disorders, and dynamic imbalance due to oxidative stress and other factors, releasing mitochondrial damage-associated molecular patterns (mt-DAMPs). These mt-DAMPs activate innate immune pathways, promote the production of type I interferons and the release of pro-inflammatory factors such as interleukin 1β, and accelerate plaque progression. Mitophagy exerts a protective effect by eliminating damaged mitochondria. Specifically, the PINK1-Parkin pathway labels damaged mitochondria through ubiquitination; mitophagy receptors (such as NIX, FUNDC1, and BNIP3) directly bind to LC3 to initiate ubiquitination-independent mitophagy; and mitochondrial-derived vesicles selectively encapsulate damaged components and target them to lysosomes for degradation. All these processes can reduce mt-DAMP-induced damage and inhibit excessive immune activation. In this review, we summarize that innate immune imbalance caused by mitochondrial damage is a key mechanism for atherosclerosis progression. Mitochondrial quality control clears damaged mitochondria through multiple pathways, alleviates inflammatory responses and plaque burden, and provides potential targets for atherosclerosis treatment. Its precise regulatory mechanisms and drug development are future research directions.