The role of mitochondrial DNA and RNA in promoting liver disease pathogenesis.

Mitochondria are a semi-autonomous organelle due to their unique structural organization and independent genetic system, and they play diverse roles in maintaining cellular homeostasis. The liver is the central metabolic organ and performs myriad functions, including energy production, metabolism, and detoxification. Liver diseases account for approximately two million mortalities per year. Mitochondrial dysfunction and damage are implicated in promoting the pathogenesis of different liver diseases. Mitochondria and mitochondrial nucleic acids, namely, mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), have emerged as regulators of innate immunity. Here, we first review the structural organization of mitochondria and the molecular mechanisms governing mitochondrial biogenesis, replication, and transcription. Next, we describe the mechanistic details by which mitochondrial dysfunction causes the release of mtDNA and mtRNA into the cytosol and extracellular milieu. Some of the mechanisms are through the opening of mitochondrial permeability transition pore (mPTP), voltage-dependent anion channel (VDAC) oligomerization, prohibitin (PHB1/2), mitochondria-derived vesicles (MDV), dysfunction of the mtRNA degradosomes, and senescence-associated secretory phenotype (SASP). Cell death pathways such as necrosis, necroptosis, and pyroptosis, in addition to perpetuating inflammation, also release mtDNA and mtRNA into the extracellular milieu. The released mtDNA and mtRNA act as damage associated molecular patterns (DAMPs) that engage various cytosolic DNA and RNA sensors and pattern recognition receptors (PRRs) such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), toll-like receptor 9 (TLR9), toll-like receptor 3 (TLR3), Z-DNA-binding protein 1 (ZBP1), NOD-like receptor protein 3 (NLRP3), absent in melanoma 2 (AIM2), retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), protein kinase R (PKR) and activate different signaling cascades downstream. This review provides a contemporary, comprehensive analysis of the available literature on the roles of mtDNA and mtRNA in liver diseases, including metabolic dysfunction-associated steatotic/steatohepatitis (MASLD/MASH), alcohol-associated liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hepatocellular carcinoma (HCC). Thus, the review highlights the potential of both mtDNA and mtRNA to serve as biomarkers of the pathological conditions of the liver, and the way the mitigation of mitochondrial dysfunction and the release of mtDNA or mtRNA can serve as potential therapeutic targets.