Oxidized LDL regulates efferocytosis through the CD36-PKM2-mtROS pathway.

Macrophage efferocytosis, the process by which phagocytes engulf and remove apoptotic cells (ACs), plays a critical role in maintaining tissue homeostasis. Efficient efferocytosis prevents secondary necrosis, mitigates chronic inflammation, and impedes atherosclerosis progression. However, the regulatory mechanisms of efferocytosis under atherogenic conditions remain poorly understood. We previously demonstrated that oxidized LDL (oxLDL), an atherogenic lipoprotein, induces mitochondrial reactive oxygen species (mtROS) in macrophages via CD36. In this study, we demonstrate that macrophage mtROS facilitate continual efferocytosis through a positive feedback mechanism. However, oxLDL disrupts continual efferocytosis by dysregulating the internalization of ACs. This disruption is mediated by an overproduction of mtROS. Mechanistically, oxLDL/CD36 signaling promotes the translocation of cytosolic PKM2 to mitochondria, facilitated by the chaperone GRP75. Mitochondrial PKM2 then binds to Complex III of the electron transport chain, inducing mtROS production. This study elucidates a novel regulatory mechanism of efferocytosis in atherosclerosis, providing potential therapeutic targets for intervention. SUMMARY: Macrophages clear apoptotic cells through a process called efferocytosis, which involves mitochondrial ROS. However, the atherogenic oxidized LDL overstimulates mitochondrial ROS via the CD36-PKM2 pathway, disrupting continual efferocytosis. This finding elucidates a novel molecular mechanism that explains defects in efferocytosis, driving atherosclerosis progression.

Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases.

Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However, specific delivery of drugs into the mitochondria is still a challenge. We present recent findings on regulators of mitochondrial dynamics and reactive oxygen species (ROS), critical factors influencing mitochondrial function in CVDs. We also discuss advancements in drug delivery strategies aimed at overcoming the technical barrier in targeting mitochondria for CVD treatment.

Atg32-dependent mitophagy sustains spermidine and nitric oxide required for heat-stress tolerance in Saccharomycescerevisiae.

In Saccharomyces cerevisiae, the selective autophagic degradation of mitochondria, termed mitophagy, is critically regulated by the adapter protein Atg32. Despite our knowledge about the molecular mechanisms by which Atg32 controls mitophagy, its physiological roles in yeast survival and fitness remains less clear. Here, we demonstrate a requirement for Atg32 in promoting spermidine production during respiratory growth and heat-induced mitochondrial stress. During respiratory growth, mitophagy-deficient yeast exhibit profound heat-stress induced defects in growth and viability due to impaired biosynthesis of spermidine and its biosynthetic precursor S-adenosyl methionine. Moreover, spermidine production is crucial for the induction of cytoprotective nitric oxide (NO) during heat stress. Hence, the re-addition of spermidine to Atg32 mutant yeast is sufficient to both enhance NO production and restore respiratory growth during heat stress. Our findings uncover a previously unrecognized physiological role for yeast mitophagy in spermidine metabolism and illuminate new interconnections between mitophagy, polyamine biosynthesis and NO signaling.