The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR

Steffen, Janos; Ngo, Jennifer; Wang, Shengping; Williams, Kevin J.; Kramer, Henning F.; Ho, G. C.; Rodríguez, Carlos J.; Yekkala, Krishna; Amuzie, Chidozie; Bialecki, Russell; Norquay, Lisa D.; Nawrocki, Andrea R.; Erion, Mark D.; Pocai, Alessandro; Liesa, Marc

doi:10.1016/j.molmet.2022.101566

Cited by 26 publications

(14 citation statements)

References 40 publications

(81 reference statements)

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“…However, this can be explained by the need to maintain the long form of the inner mitochondrial membrane fusion GTPase OPA1 (L‐OPA1) in this setting with concomitant reduction in the activity of the OMA1 protease, which can cleave OPA1 and subsequently trigger the mitochondrial integrated stress response (ISR). Another study examined the effect of mitochondrial hyperfusion and ISR hyperactivation in the context of nonalcoholic steatohepatitis (NASH) and showed that steatosis worsens upon mitochondrial elongation (Steffen et al , 2022 ). This was linked to impaired complex I activity necessary for FAO and accumulation of nonesterified fatty acids (Steffen et al , 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another study examined the effect of mitochondrial hyperfusion and ISR hyperactivation in the context of nonalcoholic steatohepatitis (NASH) and showed that steatosis worsens upon mitochondrial elongation (Steffen et al , 2022 ). This was linked to impaired complex I activity necessary for FAO and accumulation of nonesterified fatty acids (Steffen et al , 2022 ). The studies by Tondera et al and Steffen et al are but two examples in further support of our findings that the dynamic adaptation of mitochondrial morphology, whether hyperfusion or forced fragmentation, play an integral role in metabolic flexibility and cell survival in a context‐specific manner.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA

et al. 2023

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Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA

et al. 2023

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“…DRP1-mediated mitochondrial fragmentation observed in non-alcoholic fatty liver disease has been proposed to be a maladaptive process that exacerbates hepatic insulin resistance, steatohepatitis and cell death. Accordingly, both deletion and inhibition of hepatocyte-DRP1 activity in a preventative manner protected mice from high-fat diet-induced hepatic steatosis, insulin resistance and even body weight gain (Steffen et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

Mahmoud

Abdel-Aziz

Khafaga

et al. 2023

Mol Med

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Background Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on mitochondrial biogenesis in prenatal fetal liver, skeletal muscle, and placental tissues. Methods The study was conducted on 20 female albino rats divided into a control group receiving a placebo and an exposed group receiving 4 mg/kg orally/day for 3 months of Sofosbuvir. At the end of the treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle, and placental tissues. Results The results of our study indicated that the exposure of young female rats to Sofosbuvir affects pregnancy outcomes. Fetal liver and muscle showed lower mitochondrial DNA-copy number (mtDNA-CN) by about 24% and 29% respectively, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and its downstream targets; nuclear respiratory factor-1 and mitochondrial transcription factor A. While the placental tissues showed different patterns, particularly elevated in mtDNA-CN by about 43%. Conclusions The study provides preliminary evidence of the detrimental effects of Sofosbuvir on the pregnancy outcomes of the exposed females and may impair the placental and fetal organs’ development. These effects may be mediated through modulating mitochondrial homeostasis and functions.

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“…Additionally, evidence in skeletal muscle has suggested that estrogen mediates the activation of DNM1L/Drp1, a critical protein necessary for mitochondrial fission and activation of mitophagy 75 . DNML1/Drp1 was recently observed to be critical in improving diet-induced steatohepatitis, via reduced ER stress and improved mitochondrial respiratory capacity 76 . The observed decrease in DNM1L/Drp1 and BNIP3 in VCD mice supports the potential role of estrogen in maintaining hepatocyte mitophagy pathways.…”

Section: Discussionmentioning

confidence: 99%

“…was recently observed to be critical in improving diet-induced steatohepatitis, via reduced ER stress and improved mitochondrial respiratory capacity 76 . The observed decrease in DNM1L/Drp1 and BNIP3 in VCD mice supports the potential role of estrogen in maintaining hepatocyte mitophagy pathways.…”

Section: Discussionmentioning

confidence: 99%

VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism

Kumari,

Ponte,

Franczak

et al. 2023

Preprint

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Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. In this study, we treated female C57BL6/J mice with VCD (160mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions. VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS diet resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways. Our findings suggest that the VCD- induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.

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The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR

Cited by 26 publications

References 40 publications

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism

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