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Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis.Antioxidants (Basel, Switzerland) Jun 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis... (Review)
Review
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis and cirrhosis are the leading causes of liver failure and liver-related death worldwide. Mitochondria are crucial organelles in liver cells for energy generation and the oxidative metabolism of fatty acids and carbohydrates. Recently, mitochondrial dysfunction in liver cells has been shown to play a vital role in the pathogenesis of MASLD and liver fibrosis. Mitophagy, a selective form of autophagy, removes and recycles impaired mitochondria. Although significant advances have been made in understanding mitophagy in liver diseases, adequate summaries concerning the contribution of liver cell mitophagy to MASLD and liver fibrosis are lacking. This review will clarify the mechanism of liver cell mitophagy in the development of MASLD and liver fibrosis, including in hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells. In addition, therapeutic strategies or compounds related to hepatic mitophagy are also summarized. In conclusion, mitophagy-related therapeutic strategies or compounds might be translational for the clinical treatment of MASLD and liver fibrosis.
PubMed: 38929168
DOI: 10.3390/antiox13060729 -
International Journal of Molecular... Jun 2024Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we...
Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function.
Topics: Animals; DNA Polymerase gamma; Ubiquitin-Protein Ligases; Mice; DNA, Mitochondrial; Mice, Knockout; Mutation; Proteomics; Proteome; Mitochondria; Mitochondria, Liver; Mitochondrial Proteins
PubMed: 38928146
DOI: 10.3390/ijms25126441 -
Biology May 2024Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on... (Review)
Review
Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on mitohormesis, a concept proposing an adaptive response of mitochondria to minor disturbances in homeostasis, offering novel therapeutic avenues for mitochondria-related diseases. This comprehensive review explores the concept of mitohormesis, elucidating its induction mechanisms and occurrence. Intracellular molecules like reactive oxygen species (ROS), calcium, mitochondrial unfolded proteins (UPRmt), and integrated stress response (ISR), along with external factors such as hydrogen sulfide (HS), physical stimuli, and exercise, play pivotal roles in regulating mitohormesis. Based on the available evidence, we elucidate how mitohormesis maintains mitochondrial homeostasis through mechanisms like mitochondrial quality control and mitophagy. Furthermore, the regulatory role of mitohormesis in mitochondria-related diseases is discussed. By envisioning future applications, this review underscores the significance of mitohormesis as a potential therapeutic target, paving the way for innovative interventions in disease management.
PubMed: 38927274
DOI: 10.3390/biology13060394 -
Mitochondrion Jun 2024Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely... (Review)
Review
Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely regarded as the key processes involved in the aging process, which may then cause significant harm to mitochondrial DNA, leading to apoptosis. Normal circulatory function is a significant predictor of disease-free life expectancy. Indeed, disorders affecting the cardiovascular system, which are becoming more common, are the primary cause of worldwide morbidity, disability, and mortality. Cardiovascular aging may precede or possibly underpin overall, age-related health decline. Numerous studies have foundmitochondrial mechanistc approachplays a vital role in the in the onset and development of aging. The D-galactose (D-gal)-induced aging model is well recognized and commonly used in the aging study. In this review we redeposit the association of the previous and current studies on mitochondrial homeostasis and its underlying mechanisms in D-galactose cardiovascular ageing. Further we focus the novel and the treatment strategies to combat the major complication leading to the cardiovascular ageing.
PubMed: 38925493
DOI: 10.1016/j.mito.2024.101923 -
British Journal of Pharmacology Jun 2024Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer...
BACKGROUND AND PURPOSE
Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy-inducing activity of 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model.
EXPERIMENTAL APPROACH
Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt-Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH-SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae.
KEY RESULTS
PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel-induced mitochondrial dysfunction in both SH-SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel-induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction.
CONCLUSION AND IMPLICATIONS
This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy-inducing compounds.
PubMed: 38925168
DOI: 10.1111/bph.16476 -
The Journal of Physiology Jun 2024Murine models lacking CLOCK/BMAL1 proteins in skeletal muscle (SkM) present muscle deterioration and mitochondria abnormalities. It is unclear whether humans with lower...
Murine models lacking CLOCK/BMAL1 proteins in skeletal muscle (SkM) present muscle deterioration and mitochondria abnormalities. It is unclear whether humans with lower levels of these proteins in the SkM have similar alterations. Here we evaluated the association between BMAL1 and CLOCK protein mass with mitochondrial dynamics parameters and molecular and functional SkM quality markers in males. SkM biopsies were taken from the vastus lateralis of 16 male (non-athletes, non-obese and non-diabetic) subjects (8-9 a.m.). The morphology of mitochondria and their interaction with the sarcoplasmic reticulum (mitochondria-SR) were determined using transmission electron microscopy images. Additionally, protein abundance of the OXPHOS complex, mitochondria fusion/fission regulators, mitophagy and signalling proteins related to muscle protein synthesis were measured. To evaluate the quality of SkM, the cross-sectional area and maximal SkM strength were also measured. The results showed that BMAL1 protein mass was positively associated with mitochondria-SR distance, mitochondria size, mitochondria cristae density and mTOR protein mass. On the other hand, CLOCK protein mass was negatively associated with mitochondria-SR interaction, but positively associated with mitochondria complex III, OPA1 and DRP1 protein mass. Furthermore, CLOCK protein mass was positively associated with the protein synthesis signalling pathway (total mTOR, AKT and P70S6K protein mass) and SkM strength. These findings suggest that the BMAL1 and CLOCK proteins play different roles in regulating mitochondrial dynamics and SkM function in males, and that modulation of these proteins could be a potential therapeutic target for treating muscle diseases. KEY POINTS: In murine models, reductions in BMAL1 and CLOCK proteins lead to changes in mitochondria biology and a decline in muscle function. However, this association has not been explored in humans. We found that in human skeletal muscle, a decrease in BMAL1 protein mass is linked to smaller intermyofibrillar mitochondria, lower mitochondria cristae density, higher interaction between mitochondria and sarcoplasmic reticulum, and reduced mTOR protein mass. Additionally, we found that a decrease in CLOCK protein mass is associated with a higher interaction between mitochondria and sarcoplasmic reticulum, lower protein mass of OPA1 and DRP1, which regulates mitochondria fusion and fission, lower protein synthesis signalling pathway (mTOR, AKT and P70S6K protein mass), and decreased skeletal muscle strength. According to our findings in humans, which are supported by previous studies in animals, the mitochondrial dynamics and skeletal muscle function could be regulated differently by BMAL1 and CLOCK proteins. As a result, targeting the modulation of these proteins could be a potential therapeutic approach for treating muscle diseases and metabolic disorders related to muscle.
PubMed: 38922907
DOI: 10.1113/JP285955 -
Autophagy Jun 2024Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of...
Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of ameliorates skeletal muscle atrophy in various tumor-bearing mice. ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. : AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; -Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.
PubMed: 38919131
DOI: 10.1080/15548627.2024.2360340 -
Nature Structural & Molecular Biology Jun 2024Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced...
Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.
PubMed: 38918639
DOI: 10.1038/s41594-024-01338-y -
JCI Insight Jun 2024Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite...
Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite ongoing research, no effective treatments are currently available for this condition. Our study provided evidence for the pathogenicity of an unreported c.1780T>C variant in the OPA1 gene through patient-derived skin fibroblasts and an engineered HEK293T cell line with OPA1 downregulation. We demonstrated that OPA1 insufficiency promoted mitochondrial fragmentation and increased DRP1 expression, disrupting mitochondrial dynamics. Consequently, this disruption enhanced mitophagy and caused mitochondrial dysfunction, contributing to the ADOA+ phenotype. Notably, the Drp1 inhibitor, mitochondrial division inhibitor-1 (Mdivi-1), effectively mitigated the adverse effects of OPA1 impairment. These effects included reduced Drp1 phosphorylation, decreased mitochondrial fragmentation, and balanced mitophagy. Thus, we propose that intervening in DRP1 with Mdivi-1 could correct mitochondrial abnormalities, offering a promising therapeutic approach for managing ADOA+.
PubMed: 38916953
DOI: 10.1172/jci.insight.180582 -
Brain Structure & Function Jun 2024In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein...
In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment.
PubMed: 38916724
DOI: 10.1007/s00429-024-02816-1