bims-mimcad 2024-05-26 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024‒05‒26
nine papers selected by
Henver Brunetta, University of Guelph

Chemerin regulates glucose and lipid metabolism by changing mitochondrial structure and function associated with androgen/androgen receptor.
Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
Differential impact of sex on regulation of skeletal muscle mitochondrial function and protein homeostasis by hypoxia-inducible factor-1α in normoxia.
CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.
Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart.
Mitochondrial Phosphopantetheinylation is Required for Oxidative Function.
Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments.
Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression.

Am J Physiol Endocrinol Metab. 2024 May 22.

Chemerin regulates glucose and lipid metabolism by changing mitochondrial structure and function associated with androgen/androgen receptor.

Lijun Yin, Hongtai Tang, Jing Qu, Yi Jia, Qilong Zhang, Xiaohui Wang.

  The adipokine chemerin contributes to exercise-induced improvements in glucose and lipid metabolism; however, the underlying mechanism remains unclear. We aimed to confirm the impact of reduced chemerin expression on exercise-induced improvement in glycolipid metabolism in male diabetic (DM) mice through exogenous chemerin administration. Furthermore, the underlying mechanism of chemerin involved in changes in muscle mitochondria function mediated by androgen/androgen receptor (AR) was explored by generating adipose-specific and global chemerin knockout (adipo-chemerin-/- and chemerin-/-) mice. DM mice were categorized into the DM, exercised DM (EDM), and EDM + chemerin supplementation groups. Adipo-chemerin-/- and chemerin-/- mice were classified in the sedentary or exercised groups and fed either a normal or high-fat diet. Exercise mice underwent a 6-week aerobic exercise regimen. The serum testosterone and chemerin levels, glycolipid metabolism indices, mitochondrial function, and protein levels involved in mitochondrial biogenesis and dynamics were measured. Notably, exogenous chemerin reversed exercise-induced improvements in glycolipid metabolism, AR protein levels, mitochondrial biogenesis, and mitochondrial fusion in DM mice. Moreover, adipose-specific chemerin knockout improved glycolipid metabolism, enhanced exercise-induced increases in testosterone and AR levels in exercised mice, and alleviated the detrimental effects of a high-fat diet on mitochondrial morphology, biogenesis, and dynamics. Finally, similar improvements in glucose metabolism (but not lipid metabolism), mitochondrial function, and mitochondrial dynamics were observed in chemerin-/- mice. In conclusion, decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, likely through changes in androgen/AR signaling.

Keywords:  aerobic exercise; androgen; chemerin; glucose and lipid metabolism; mitochondria

DOI:  https://doi.org/10.1152/ajpendo.00104.2023
J Biol Chem. 2024 May 21. pii: S0021-9258(24)01904-5. [Epub ahead of print] 107403

Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.

Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.

Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.

DOI: https://doi.org/10.1016/j.jbc.2024.107403
J Physiol. 2024 May 18.

Differential impact of sex on regulation of skeletal muscle mitochondrial function and protein homeostasis by hypoxia-inducible factor-1α in normoxia.

Nicole Welch, Saurabh Mishra, Annette Bellar, Pugazhendhi Kannan, Amrit Gopan, Maryam Goudarzi, Jasmine King, Mathew Luknis, Ryan Musich, Vandana Agrawal, James Bena, Cameron J Koch, Ling Li, Belinda Willard, Yatrik M Shah, Srinivasan Dasarathy.

  Hypoxia-inducible factor (HIF)-1α is continuously synthesized and degraded in normoxia. During hypoxia, HIF1α stabilization restricts cellular/mitochondrial oxygen utilization. Cellular stressors can stabilize HIF1α even during normoxia. However, less is known about HIF1α function(s) and sex-specific effects during normoxia in the basal state. Since skeletal muscle is the largest protein store in mammals and protein homeostasis has high energy demands, we determined HIF1α function at baseline during normoxia in skeletal muscle. Untargeted multiomics data analyses were followed by experimental validation in differentiated murine myotubes with loss/gain of function and skeletal muscle from mice without/with post-natal muscle-specific Hif1a deletion (Hif1amsd). Mitochondrial oxygen consumption studies using substrate, uncoupler, inhibitor, titration protocols; targeted metabolite quantification by gas chromatography-mass spectrometry; and post-mitotic senescence markers using biochemical assays were performed. Multiomics analyses showed enrichment in mitochondrial and cell cycle regulatory pathways in Hif1a deleted cells/tissue. Experimentally, mitochondrial oxidative functions and ATP content were higher with less mitochondrial free radical generation with Hif1a deletion. Deletion of Hif1a also resulted in higher concentrations of TCA cycle intermediates and HIF2α proteins in myotubes. Overall responses to Hif1amsd were similar in male and female mice, but changes in complex II function, maximum respiration, Sirt3 and HIF1β protein expression and muscle fibre diameter were sex-dependent. Adaptive responses to hypoxia are mediated by stabilization of constantly synthesized HIF1α. Despite rapid degradation, the presence of HIF1α during normoxia contributes to lower mitochondrial oxidative efficiency and greater post-mitotic senescence in skeletal muscle. In vivo responses to HIF1α in skeletal muscle were differentially impacted by sex. KEY POINTS: Hypoxia-inducible factor -1α (HIF1α), a critical transcription factor, undergoes continuous synthesis and proteolysis, enabling rapid adaptive responses to hypoxia by reducing mitochondrial oxygen consumption. In mammals, skeletal muscle is the largest protein store which is determined by a balance between protein synthesis and breakdown and is sensitive to mitochondrial oxidative function. To investigate the functional consequences of transient HIF1α expression during normoxia in the basal state, myotubes and skeletal muscle from male and female mice with HIF1α knockout were studied using complementary multiomics, biochemical and metabolite assays. HIF1α knockout altered the electron transport chain, mitochondrial oxidative function, signalling molecules for protein homeostasis, and post-mitotic senescence markers, some of which were differentially impacted by sex. The cost of rapid adaptive responses mediated by HIF1α is lower mitochondrial oxidative efficiency and post-mitotic senescence during normoxia.

Keywords:  hypoxia inducible factor‐1 alpha; muscle‐specific deletion; normoxia; physiology; sex‐differences

DOI:  https://doi.org/10.1113/JP285339
Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2405123121

CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.

Rachel Nechushtai, Linda Rowland, Ola Karmi, Henri-Baptiste Marjault, Thi Thao Nguyen, Shubham Mittal, Raheel S Ahmed, DeAna Grant, Camila Manrique-Acevedo, Faruck Morcos, José N Onuchic, Ron Mittler.

  Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.

Keywords:  Duchenne muscular dystrophy; NDUFV2; NEET/CISD proteins; complex I; mitochondria

DOI:  https://doi.org/10.1073/pnas.2405123121
Nat Commun. 2024 May 20. 15(1): 4277

Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart.

Yu Jin Chung, Zoe Hoare, Friedrich Baark, Chak Shun Yu, Jia Guo, William Fuller, Richard Southworth, Doerthe M Katschinski, Michael P Murphy, Thomas R Eykyn, Michael J Shattock.

Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb's free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.

DOI: https://doi.org/10.1038/s41467-024-48474-z
bioRxiv. 2024 May 10. pii: 2024.05.09.592977. [Epub ahead of print]

Mitochondrial Phosphopantetheinylation is Required for Oxidative Function.

Pieter R Norden, Riley J Wedan, Jacob Z Longenecker, Samuel E J Preston, Naomi Graber, Olivia Ols, Morgan Canfield, Elizabeth McLaughlin, Sara M Nowinski.

Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in Aasdhppt that are likely pathogenic in humans.

DOI: https://doi.org/10.1101/2024.05.09.592977
Circ Res. 2024 May 24. 134(11): 1581-1606

Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments.

Antentor O Hinton, Alhaji U N'jai, Zer Vue, Celestine Wanjalla.

  HIV infection and antiretroviral therapy alter mitochondrial function, which can progressively lead to mitochondrial damage and accelerated aging. The interaction between persistent HIV reservoirs and mitochondria may provide insight into the relatively high rates of cardiovascular disease and mortality in persons living with HIV. In this review, we explore the intricate relationship between HIV and mitochondrial function, highlighting the potential for novel therapeutic strategies in the context of cardiovascular diseases. We reflect on mitochondrial dynamics, mitochondrial DNA, and mitochondrial antiviral signaling protein in the context of HIV. Furthermore, we summarize how toxicities related to early antiretroviral therapy and current highly active antiretroviral therapy can contribute to mitochondrial dysregulation, chronic inflammation, and poor clinical outcomes. There is a need to understand the mechanisms and develop new targeted therapies. We further consider current and potential future therapies for HIV and their interplay with mitochondria. We reflect on the next-generation antiretroviral therapies and HIV cure due to the direct and indirect effects of HIV persistence, associated comorbidities, coinfections, and the advancement of interdisciplinary research fields. This includes exploring novel and creative approaches to target mitochondria for therapeutic intervention.

Keywords:  aging; antiretroviral therapy; inflammation; mitochondrial dynamics; myocardial infarction

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324296
Nat Commun. 2024 May 18. 15(1): 4244

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Nathan P Ward, Sang Jun Yoon, Tyce Flynn, Amanda M Sherwood, Maddison A Olley, Juliana Madej, Gina M DeNicola.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.

DOI: https://doi.org/10.1038/s41467-024-48695-2
Redox Biol. 2024 May 17. pii: S2213-2317(24)00170-8. [Epub ahead of print]73 103192

Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression.

Thomas Olsen, Kathrine J Vinknes, Kristýna Barvíková, Emma Stolt, Sindre Lee-Ødegård, Hannibal Troensegaard, Hanna Johannessen, Amany Elshorbagy, Jitka Sokolová, Jakub Krijt, Michaela Křížková, Tamás Ditrói, Péter Nagy, Bente Øvrebø, Helga Refsum, Magne Thoresen, Kjetil Retterstøl, Viktor Kožich.

  BACKGROUND: In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue.AIM: To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression.
METHODS: Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR.
RESULTS: SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and β-oxidation (FDR = 0.02).
CONCLUSION: SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders. TRIAL IDENTIFIER: https://clinicaltrials.gov/study/NCT04701346.

Keywords:  Adipose tissue; Cysteine; Gene expression; Hydrogen sulfide; Methionine; Randomized controlled trial; Sulfur amino acid restriction; Transsulfuration

DOI:  https://doi.org/10.1016/j.redox.2024.103192