Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles

Koves, Timothy R.; Zhang, Guofang; Davidson, Michael T.; Chaves, Alec; Crown, Scott B.; Johnson, Jordan M.; Slentz, Dorothy H.; Grimsrud, Paul A.; Muoio, Deborah M.

doi:10.1016/j.cmet.2023.03.016

Cited by 15 publications

(5 citation statements)

References 67 publications

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“…Taken together, these studies suggests that autophagy/mitophagy is not essential for basal cardiac function, but is necessary for situations in which there is a mismatch in energy supply and demand. This finding is in keeping with recent studies indicating that mitochondrial flexibility is necessary to maintain energy stability and muscle function in conditions with high demand to fuel ratios 60 .…”

Section: Discussionsupporting

confidence: 92%

GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

Zhu,

Combs,

Liu

et al. 2023

Nat Commun

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The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.

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Section: Discussionsupporting

confidence: 92%

GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

Zhu,

Combs,

Liu

et al. 2023

Nat Commun

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“…4 a). NAD is a major component of mitochondrial respiratory chain I and is also an important material for oxidative phosphorylation [ 16 , 17 ]. NADH is also a classical antioxidant that reduces the damage caused by ROS.…”

Section: Resultsmentioning

confidence: 99%

Maresin1 alleviates liver ischemia/reperfusion injury by reducing liver macrophage pyroptosis

Zeng

Xian

et al. 2023

J Transl Med

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Background Cell pyroptosis has a strong proinflammatory effect, but it is unclear whether pyroptosis of liver macrophages exacerbates liver tissue damage during liver ischemia‒reperfusion (I/R) injury. Maresin1 (MaR1) has a strong anti-inflammatory effect, and whether it can suppress liver macrophage pyroptosis needs further study. Methods This study aimed to investigate whether MaR1 can alleviate liver I/R injury by inhibiting macrophage pyroptosis. The effects of MaR1 on cell pyroptosis and mitochondrial damage were studied by dividing cells into control, hypoxia/reoxygenation, and hypoxia/reoxygenation + MaR1 groups. Knocking out RORa was used to study the mechanism by which MaR1 exert its protective effects. Transcriptome analysis, qRT‒PCR and Western blotting were used to analyze gene expression. Untargeted metabolomics techniques were used to analyze metabolite profiles in mice. Flow cytometry was used to assess cell death and mitochondrial damage. Results We first found that MaR1 significantly reduced liver I/R injury. We observed that MaR1 decreased liver I/R injury by inhibiting liver macrophage pyroptosis. Then, we discovered that MaR1 promotes mitochondrial oxidative phosphorylation, increases the synthesis of ATP, reduces the generation of ROS, decreases the impairment of mitochondrial membrane potential and inhibits the opening of mitochondrial membrane permeability transition pores. MaR1 inhibits liver macrophage pyroptosis by protecting mitochondria. Finally, we found that MaR1 exerts mitochondrial protective effects through activation of its nuclear receptor RORa and the PI3K/AKT signaling pathway. Conclusions During liver I/R injury, MaR1 can reduce liver macrophage pyroptosis by reducing mitochondrial damage, thereby reducing liver damage.

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“…Another plausible explanation is that fatty acids not completely metabolized (i.e., incomplete fatty acid oxidation) lead to PDH enzyme activity inhibition. Koves et al 34 demonstrated that incomplete fatty acid oxidation is detrimental to pyruvate oxidation and that restricted PDH activity can reduce fatty acid oxidation. The conceptual framework proposed by the authors is that a crucial co‐factor (i.e., free CoA) required for long‐chain fatty acid oxidation is maintained by reverse flux of pyruvate‐mediated acetyl‐CoA via the medium‐chain ketothiolase (MCK) and that this reverse flux process is permissible in the presence of short‐chain carbons.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of Western diet and traumatic muscle injury on skeletal muscle metabolic regulation in male and female mice

Heo,

Schifino,

McFaline‐Figueroa

et al. 2023

J cachexia sarcopenia muscle

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BackgroundThis study was designed to develop an understanding of the pathophysiology of traumatic muscle injury in the context of Western diet (WD; high fat and high sugar) and obesity. The objective was to interrogate the combination of WD and injury on skeletal muscle mass and contractile and metabolic function.MethodsMale and female C57BL/6J mice were randomized into four groups based on a two‐factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured + NC, uninjured + WD, VML + NC and VML + WD at 8 weeks of intervention.ResultsVML‐injured male and female mice both exhibited decrements in muscle mass (−17%, P < 0.001) and muscle strength (−28%, P < 0.001); however, VML + WD females had a 28% greater muscle mass compared to VML + NC females (P = 0.034), a compensatory response not detected in males. VML‐injured male and female mice both had lower carbohydrate‐ and fat‐supported muscle mitochondrial respiration (JO2) and less electron conductance through the electron transport system (ETS); however, male VML–WD had 48% lower carbohydrate‐supported JO2 (P = 0.014) and 47% less carbohydrate‐supported electron conductance (P = 0.026) compared to male VML + NC, and this diet–injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML + WD had 31% less complex I activity (P = 0.004) and 43% less complex II activity (P = 0.005) compared to male VML + NC. This was a diet–injury phenotype not present in females. Pyruvate dehydrogenase (PDH), β‐hydroxyacyl‐CoA dehydrogenase, citrate synthase, α‐ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired JO2 in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post‐translational regulation of PDH. PDH enzyme activity was 24% less in VML‐injured males, independent of diet (P < 0.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine‐293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho‐PDHser293 and phospho‐PDH‐to‐total PDH ratio in WD mice compared to NC, independent of injury (P ≤ 0.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (P = 0.025), and was complemented by greater phospho‐PDHser293 (P = 0.001).ConclusionsMales are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.

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Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles

Cited by 15 publications

References 67 publications

GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

Maresin1 alleviates liver ischemia/reperfusion injury by reducing liver macrophage pyroptosis

Differential effects of Western diet and traumatic muscle injury on skeletal muscle metabolic regulation in male and female mice

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