Understanding Dysfunctional Autophagy and Mitophagy in Inflammatory Cardiovascular Disease

Mitochondria are critical cellular powerhouses that produce adenosine triphosphate to maintain the structure and integrity of the cell. Mitochondria generate 90% of the energy of a cell. Chronic inflammation causes damage to mitochondria. When enough mitochondria are dysfunctional, the involved organ will suffer. Mitochondria become dysfunctional in the setting of chronic inflammation. Under noninflammatory conditions, the body generates new mitochondria (mitochondrial biogenesis) and removes old and damaged mitochondria via mitophagy. When mitochondria are damaged, they "spontaneously" leak out reactive oxygen species, mitochondrial DNA, and damage-associated molecular patterns, generating erroneous innate immune responses. Autophagy is a recycling and housekeeping process that removes dysfunctional components, organelles, and proteins, promoting the recovery and maintenance of cell health. Mitophagy is a specific variant of this process that removes dysfunctional mitochondria from the cell. Mitophagy declines with age, allowing dysfunctional mitochondria to accumulate, and chronic inflammation leads to cardiovascular disease (CVD). In CVD, impairment of both autophagy and mitophagy leads to more chronic inflammation, characterized by hyperactivation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a key component of the immune system. Once activated, it triggers inflammation, leading to excessive cytokine activity, proinflammatory macrophage polarization, pyroptosis, and increased immune cell infiltration into cardiac and vascular tissues. Pyroptosis is a form of inflammatory cell death triggered by programmed cues; however, in autoimmunity and cancer, when overactivated, this process can become detrimental. Adequate regulation of these events reduces oxidative stress, inflammatory cascades, fibrosis, and maladaptive remodeling, thereby improving overall cardiovascular health. Targeted therapeutic enhancement of autophagy and mitophagy represents a promising strategy to modulate immune-driven pathology and improve outcomes in cardiovascular conditions. We will review the mechanisms of how this inflammation causes CVD.