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Programmed cell death and innate immunity

Programmed cell death (PCD) is crucial for various physiological functions, including organ development and cellular homeostasis. It serves as an intrinsic mechanism to prevent malignant transformation and plays a fundamental role in immunity by aiding in antiviral defense, pathogen elimination, inflammation, and immune cell recruitment.

Mitochondria have long been recognized for their central role in the intrinsic pathway of apoptosis, a form of PCD. In recent decades, they have also been identified as a signalling hub for much of the innate immune system. The endosymbiotic origin of mitochondria distinguishes them from other cellular components, and the exposure of mitochondrial elements to the cytosol can trigger the same pathways as infection markers. These pathways lead to apoptosis, autophagy, or the induction of proinflammatory genes.

Mitochondria contribute to apoptosis by releasing cytochrome c, which directly induces the formation of apoptosomes. Additionally, they are a source of various damage-associated molecular patterns (DAMPs). These DAMPs are often recognised by the same pattern-recognition receptors (PRRs) that respond to pathogen-associated molecular patterns (PAMPs) during infections. For example, mitochondrial mtDNA resembles bacterial DNA due to its lack of CpG methylation and can be detected by Toll-like receptor 9 and cGAS. Double-stranded RNA (dsRNA), produced due to bidirectional mitochondrial transcription, can activate viral sensing pathways through RIG-I-like receptors. Additionally, the N -formylation of mitochondrial proteins, similar to that of bacterial proteins, can be recognized by formyl peptide receptors.

Normally, these mitochondrial components are sequestered from the rest of the cell but are released following mitochondrial membrane permeabilization during apoptosis or passively after mitochondrial damage. However, mitochondria also play an active role in innate immunity, releasing mtDNA in response to metabolic cues. Mitochondria are also the localization site for immune and apoptosis regulatory proteins, such as BAX, MAVS (located on the outer membrane), and NLRX1 (found in the matrix). These proteins are modulated by the mitochondrial metabolic status and mitochondrial dynamics.