bims-mimcad 2024-05-19 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–05–19
ten papers selected by
Henver Brunetta, University of Guelph

MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.
Biological sex, sex steroids and sex chromosomes contribute to mouse cardiac aging.
Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.
Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
Mitochondrial heterogeneity and adaptations to cellular needs.
2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.
FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration.
Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.
Serine synthesis controls mitochondrial biogenesis in macrophages.

Circ Res. 2024 May 15.

MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.

Barbara Roman, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia C Liu, Elizabeth Murphy.

   BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.
METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
RESULTS: Knock out MICU3 hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, overexpression of MICU3 hearts exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, overexpression of MICU3 animals exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in overexpression of MICU3 hearts compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.

Keywords:  calcium; cardiomegaly; echocardiography; mitochondria; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324026
J Mol Cell Cardiol. 2024 May 09. pii: S0022-2828(24)00069-5. [Epub ahead of print]192 36-47

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.

Aubrey C Cantrell, Jessie Besanson, Quinesha Williams, Ngoc Hoang, Kristin Edwards, G Reid Bishop, Yingjie Chen, Heng Zeng, Jian-Xiong Chen.

   AIMS: Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction.
METHODS AND RESULTS: Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron‑sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity.
CONCLUSIONS: Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron‑sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Keywords:  Cardiomyopathy; Ferroptosis; Friedreich's ataxia; Mitochondrial dysfunction; SIRT3

DOI:  https://doi.org/10.1016/j.yjmcc.2024.05.003
Aging (Albany NY). 2024 May 13. 16

Biological sex, sex steroids and sex chromosomes contribute to mouse cardiac aging.

Audrey Morin-Grandmont, Élisabeth Walsh-Wilkinson, Emylie-Ann Labbé, Sara-Ève Thibodeau, Élizabeth Dupont, Dominique K Boudreau, Marie Arsenault, Yohan Bossé, Jacques Couet.

  After menopause, the incidence of cardiovascular disease rapidly rises in women. The disappearing protection provided by sex steroids is a consequence of the development of many risk factors. Preclinical studies are necessary to understand better the effects of ovarian hormones loss cardiac aging. To mimic menopause in mice and study its consequences, we delayed ovariectomy at 12 months and followed animals for 12 months. Using RNA sequencing, we investigated changes in the myocardial exome with aging. In addition, with four-core genotypes (FCG) transgenic mice, we studied sex chromosome effects on cardiac aging. Heart weight increased from 3 to 24 months (males + 35%, females + 29%). In males, 75% of this increase had occurred at 12 months; in females, only 30%. Gonadectomy of mice at 12 months blocked cardiac hypertrophy in both sexes during the second year of life. The dosage of the X chromosomes did not influence cardiac growth in young and older mice. We performed an RNA sequencing study in young and old mice. We identified new highly expressed genes modulated during aging (Bdh, Myot, Cpxm2, and Slc38a1). The myocardial exome in older animals displayed few differences related to the animal's sex or the presence or absence of sex steroids for a year. We show that the morphological evolution of the heart depends on the biological sex via gonadal sex hormone actions. The myocardial exome of old male and female mice is relatively similar. Our study emphasizes the need to consider sex steroid effects in studying cardiac aging.

Keywords:  aging; cardiac hypertrophy; heart failure; hypertension; mouse; sex differences

DOI:  https://doi.org/10.18632/aging.205822
J Adv Res. 2024 May 12. pii: S2090-1232(24)00173-5. [Epub ahead of print]

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

Yu Zhao, Zongshi Lu, Hexuan Zhang, Lijuan Wang, Fang Sun, Qiang Li, Tingbing Cao, Bowen Wang, Huan Ma, Mei You, Qing Zhou, Xiao Wei, Li Li, Yingying Liao, Zhencheng Yan, Daoyan Liu, Peng Gao, Zhiming Zhu.

   INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive.
OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms.
METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms.
RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy.
CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Keywords:  Cardiac hypertrophy; High salt intake; Metabolic reprogramming; SIRT3; Sodium-glucose exchanger 2 inhibitors

DOI:  https://doi.org/10.1016/j.jare.2024.04.030
iScience. 2024 May 17. 27(5): 109808

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.

Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.

  Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.

Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109808
Nat Cell Biol. 2024 May;26(5): 674-686

Mitochondrial heterogeneity and adaptations to cellular needs.

Melia Granath-Panelo, Shingo Kajimura.

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

DOI: https://doi.org/10.1038/s41556-024-01410-1
Signal Transduct Target Ther. 2024 May 15. 9(1): 133

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.

Fu Peng, Minru Liao, Wenke Jin, Wei Liu, Zixiang Li, Zhichao Fan, Ling Zou, Siwei Chen, Lingjuan Zhu, Qian Zhao, Gu Zhan, Liang Ouyang, Cheng Peng, Bo Han, Jin Zhang, Leilei Fu.

Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

DOI: https://doi.org/10.1038/s41392-024-01816-1
J Biol Chem. 2024 May 10. pii: S0021-9258(24)01860-X. [Epub ahead of print] 107359

FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration.

Rabab El-Mergawy, Lexie Chafin, Jose A Ovando-Ricardez, Lorena Rosa, MuChun Tsai, Mauricio Rojas, Ana L Mora, Rama K Mallampalli.

  FOXK2 is a crucial transcription factor implicated in a wide array of biological activities and yet understanding of its molecular regulation at the level of protein turnover is limited. Here we identify that FOXK2 undergoes degradation in lung epithelia in the presence of the virulent pathogens P. aeruginosa and K. pneumoniae through ubiquitin-proteasomal processing. FOXK2 through its carboxyl-terminus (aa 428-478) binds the Skp-Cullin-F-box ubiquitin E3 ligase subunit FBXO24 that mediates multisite polyubiquitylation of the transcription factor resulting in its nuclear degradation. FOXK2 was detected within mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxyl-terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to wild-type littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.

Keywords:  FBXO24; FOXK2; mitochondria; ubiquitylation

DOI:  https://doi.org/10.1016/j.jbc.2024.107359
Basic Res Cardiol. 2024 May 17.

Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.

Ling Li, Bernd Niemann, Fabienne Knapp, Sebastian Werner, Christian Mühlfeld, Jan Philipp Schneider, Liane M Jurida, Nicole Molenda, M Lienhard Schmitz, Xiaoke Yin, Manuel Mayr, Rainer Schulz, Michael Kracht, Susanne Rohrbach.

  The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.

Keywords:  Heart failure; Hypertrophy; LV; Mitochondria; RV

DOI:  https://doi.org/10.1007/s00395-024-01051-3
Sci Adv. 2024 May 17. 10(20): eadn2867

Serine synthesis controls mitochondrial biogenesis in macrophages.

Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.

DOI: https://doi.org/10.1126/sciadv.adn2867