Abstract
Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.
Highlights
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Out of the known ~1500 mitochondrial proteins, only 13 peptides, all involved in the oxidative phosphorylation (OXPHOS) system, are encoded in the mitochondrial circular genome, while the rest are encoded by the nuclear genome and need to be trafficked from the cytoplasm, underscoring the marked dependence of mitochondria on their cellular counterpart [3]
Proper communication between mitochondria and the nucleus—known as retrograde signaling—is essential for cellular function and the survival of the organism [4]. Mutations in both mtDNA and nuclear genes that constitute the mitochondrial proteome are responsible for primary mitochondrial disorders (PMD), a group of highly heterogeneous debilitating human conditions, hallmarked by faulty oxidative phosphorylation (OXPHOS), which affect around 1 in 5000 births [5]
Summary
Cellular complexity could not have been possible without mitochondria, resulting from the engulfment of a proteobacterium by the precursor of the eukaryotic cell around two billion years ago [1]. Proper communication between mitochondria and the nucleus—known as retrograde signaling—is essential for cellular function and the survival of the organism [4] Mutations in both mtDNA and nuclear genes that constitute the mitochondrial proteome are responsible for primary mitochondrial disorders (PMD), a group of highly heterogeneous debilitating human conditions, hallmarked by faulty oxidative phosphorylation (OXPHOS), which affect around 1 in 5000 births [5]. It has long been suggested that mitochondria-induced insults, such as proteotoxic or oxidative stress, participate in mitochondrial dysfunction [13,20], but the underlying mechanistic correlates of neuronal vulnerability to mitochondrial dysfunction are far from being elucidated In this regard, it has become increasingly evident that the endosymbiotic nature of mitochondria poses a pathogenic risk to eukaryotic cells and may contribute to disease progression [21]. These distinctive features make mtDNA an ideal target to be mis-identified as a foreign entity by innate immune sensors
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