Aug 2026· Pharmacological Research· pp.
108410
· 0 citations· 170 references
Medicine
TL;DR
It is highlighted that dysregulated mitophagy and mitochondrial fragmentation promote lipid accumulation and inflammation, whereas the abnormal formation of mitochondria-associated membranes (MAMs) exacerbates calcium overload and oxidative stress, and short-chain fatty acids and bile acids derived from the gut differentially modulate mitochondrial bioenergetics.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to liver mitochondrial dysfunction, which is driven not as an isolated event but by a self-amplifying injury loop involving impaired intrinsic quality control, aberrant organelle crosstalk, and dysregulated gut-liver signaling. This review summarizes findings in three interconnected regulatory layers: (1) intrinsic mitochondrial quality control (MQC) (PINK1/Parkin- and BNIP3/NIX-mediated mitophagy, Drp1/Mfn-driven dynamics, and chaperone/protease-maintained proteostasis); (2) organelle interactions (ER-mitochondria contacts, lipid droplet tethering, and lysosome crosstalk); and (3) extrinsic modulation via the gut-derived metabolites. We highlight that dysregulated mitophagy and mitochondrial fragmentation promote lipid accumulation and inflammation, whereas the abnormal formation of mitochondria-associated membranes (MAMs) exacerbates calcium overload and oxidative stress. Furthermore, short-chain fatty acids and bile acids derived from the gut differentially modulate mitochondrial bioenergetics. Preclinical evidence indicates that restoring MQC or targeting organelle interactions can improve MASLD symptoms. Given the multifactorial nature of MASLD, single-target interventions are insufficient; multi-target strategies and tissue-specific delivery are essential for clinical translation.
It is concluded that targeting inter-organelle interfaces, rather than isolated metabolic reactions, offers a genetically supported and mechanistically rational path forward in MASH.
Shanzab Noor, Yuan Tian, Wen Su· Frontiers in Cell and Develo...· 0 citations
This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming, and critically examines how mitochondria act as signaling hubs for inter-organ crosstalk.
It is discussed how circulating metabolites and mtDNA could serve as candidate monitoring biomarkers to turn this conceptual network into a testable, quantitative model and a multi-dimensional research framework while stressing that any clinical application must await prospective validation.
Ya-Chao Li, Huai-Jue Qiu, Xiang Gao et al.· Frontiers in Immunology· 0 citations
Mitochondrial quality control (QC) comprises interconnected pathways that preserve organelle function by detecting damage and mediating repair, remodelling, or elimination of defective components. Although many sub-organellar QC mechanisms are well characterised, stress is often sensed first at the level of mitochondrial function rather than at individual molecular targets. Functional domains such as oxidative folding, bioenergetics, redox balance, pH, and thermogenesis act as sensory portals that detect perturbations and trigger adaptive reprogramming of mitochondrial activity. In this perspective, we provide a conceptual perspective for mitochondrial QC as a mechanistically integrated network, emphasising how changes in these functional states couple diverse QC modules—including proteases, antioxidant systems, mitochondrial dynamics, mitophagy, and mitochondrial-derived vesicles—into a unified surveillance system. We propose that primary stressors, such as redox imbalance, are progressively converted into secondary stress signals, including reactive oxygen species accumulation, membrane depolarisation, metabolite redistribution, and altered lipid or nucleic-acid structure. These secondary signals propagate across mitochondrial and cytosolic compartments, amplifying QC by coordinating the engagement of repair, remodelling, and organelle-elimination pathways. This cascading transformation of stress signals not only limits the impact of the initial insult but also enhances adaptive capacity by driving synergistic deployment of QC processes across multiple mechanistic layers.
Fulya Ozcan, Filip Vujovic, Ramin M. Farahani· Biomolecules· 1 citation
Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
D. Eberhardt, Emma C. Rekate, Yasmin B. Masini et al.· Journal of Clinical Investig...· 0 citations
Although mtISR has been characterized in primary mitochondrial myopathies, secondary mitochondrial dysfunction in neuromuscular disorders suggests that mtISR-related pathways may also be activated in these conditions, and its roles in skeletal muscle pathology are discussed.
İsra Şinik, Evrim Aksu-Mengeş, B. Balci-Hayta· Bratislava Medical Journal· 0 citations
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