bims-mimcad 2024-02-04 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–02–04
six papers selected by
Henver Brunetta, University of Guelph

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.
Mitochondrial involvement in sarcopenia.
Exercise-inducible circulating extracellular vesicle irisin promotes browning and the thermogenic program in white adipose tissue.
Effects of 30 days bed rest and exercise countermeasures on PBMC bioenergetics.
The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions.

Nat Metab. 2024 Jan 29.

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.

Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey E Rhyne, Jiaxin Qian, Chao-Wei Hung, Peng Zhao, Ying Jones, Hui Gao, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Mikael Rydén, Martin Wabitsch, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg, Shannon M Reilly, Jianfeng Huang, Alan R Saltiel.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

DOI: https://doi.org/10.1038/s42255-024-00978-0
Acta Physiol (Oxf). 2024 Feb 02. e14107

Mitochondrial involvement in sarcopenia.

Charles Affourtit, Jane E Carré.

  Sarcopenia lowers the quality-of-life for millions of people across the world, as accelerated loss of skeletal muscle mass and function contributes to both age- and disease-related frailty. Physical activity remains the only proven therapy for sarcopenia to date, but alternatives are much sought after to manage this progressive muscle disorder in individuals who are unable to exercise. Mitochondria have been widely implicated in the etiology of sarcopenia and are increasingly suggested as attractive therapeutic targets to help restore the perturbed balance between protein synthesis and breakdown that underpins skeletal muscle atrophy. Reviewing current literature, we note that mitochondrial bioenergetic changes in sarcopenia are generally interpreted as intrinsic dysfunction that renders muscle cells incapable of making sufficient ATP to fuel protein synthesis. Based on the reported mitochondrial effects of therapeutic interventions, however, we argue that the observed bioenergetic changes may instead reflect an adaptation to pathologically decreased energy expenditure in sarcopenic muscle. Discrimination between these mechanistic possibilities will be crucial for improving the management of sarcopenia.

Keywords:  cellular bioenergetics; sarcopenia; skeletal muscle mitochondria

DOI:  https://doi.org/10.1111/apha.14107
Acta Physiol (Oxf). 2024 Jan 30. e14103

Exercise-inducible circulating extracellular vesicle irisin promotes browning and the thermogenic program in white adipose tissue.

Hongwei Shi, Xiaojing Hao, Yaqin Sun, Yating Zhao, Yue Wang, Xiaorui Cao, Zeen Gong, Shusen Ji, Jiayin Lu, Yi Yan, Xiuju Yu, Xiaomao Luo, Juan Wang, Haidong Wang.

   AIM: Exercise can reduce body weight and promote white fat browning, but the underlying mechanisms remain largely unknown. This study investigated the role of fibronectin type III domain-containing protein 5 (FNDC5)/Irisin, a hormone released from exercising muscle, in the browning of white fat in circulating extracellular vesicles (EVs).
METHODS: Mice were subjected to a 4 weeks of running table exercise, and fat browning was analyzed via histology, protein blotting and qPCR. Circulating EVs were extracted by ultrahigh-speed centrifugation, and ELISA was used to measure the irisin concentration in the circulating EVs. Circulating EVs that differentially expressed irisin were applied to adipocytes, and the effect of EV-irisin on adipocyte energy metabolism was analyzed by immunofluorescence, protein blotting, and cellular oxygen consumption rate analysis.
RESULTS: During sustained exercise, the mice lost weight and developed fat browning. FNDC5 was induced, cleaved, and secreted into irisin, and irisin levels subsequently increased in the plasma during exercise. Interestingly, irisin was highly expressed in circulating EVs that effectively promoted adipose browning. Mechanistically, the circulating EV-irisin complex is transported intracellularly by the adipocyte membrane receptor integrin αV, which in turn activates the AMPK signaling pathway, which is dependent on mitochondrial uncoupling protein 1 to cause mitochondrial plasmonic leakage and promote heat production. After inhibition of the AMPK signaling pathway, the effects of the EV-irisin on promoting fat browning were minimal.
CONCLUSION: Exercise leads to the accumulation of circulating EV-irisin, which enhances adipose energy metabolism and thermogenesis and promotes white fat browning in mice, leading to weight loss.

Keywords:  AMPK; browning; exercise; extracellular vesicle; integrin αV; irisin

DOI:  https://doi.org/10.1111/apha.14103
Acta Physiol (Oxf). 2024 Jan 31. e14102

Effects of 30 days bed rest and exercise countermeasures on PBMC bioenergetics.

F-M Buescher, M T Schmitz, T Frett, J Kramme, L de Boni, E M Elmenhorst, E Mulder, S Moestl, K Heusser, P Frings-Meuthen, J Jordan, J Rittweger, D Pesta.

   AIM: Altered mitochondrial function across various tissues is a key determinant of spaceflight-induced physical deconditioning. In comparison to tissue biopsies, blood cell bioenergetics holds promise as a systemic and more readily accessible biomarker, which was evaluated during head-down tilt bed rest (HDTBR), an established ground-based analog for spaceflight-induced physiological changes in humans. More specifically, this study explored the effects of HDTBR and an exercise countermeasure on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs).
METHODS: We subjected 24 healthy participants to a strict 30-day HDTBR protocol. The control group (n = 12) underwent HDTBR only, while the countermeasure group (n = 12) engaged in regular supine cycling exercise followed by veno-occlusive thigh cuffs post-exercise for 6 h. We assessed routine blood parameters 14 days before bed rest, the respiratory capacity of PBMCs via high-resolution respirometry, and citrate synthase activity 2 days before and at day 30 of bed rest. We confirmed PBMC composition by flow cytometry.
RESULTS: The change of the PBMC maximal oxidative phosphorylation capacity (OXPHOS) amounted to an 11% increase in the countermeasure group, while it decreased by 10% in the control group (p = 0.04). The limitation of OXPHOS increased in control only while other respiratory states were not affected by either intervention. Correlation analysis revealed positive associations between white blood cells, lymphocytes, and basophils with PBMC bioenergetics in both groups.
CONCLUSION: This study reveals that a regular exercise countermeasure has a positive impact on PBMC mitochondrial function, confirming the potential application of blood cell bioenergetics for human spaceflight.

Keywords:  PBMC; blood cell bioenergetics; countermeasure; exercise; head-down tilt bed rest; mitochondrial function; simulated microgravity; spaceflight

DOI:  https://doi.org/10.1111/apha.14102
J Biol Chem. 2024 Jan 30. pii: S0021-9258(24)00078-4. [Epub ahead of print] 105702

The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.

Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.

  Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly six-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.

Keywords:  BT2; ROS production; branched-chain amino acids; cardiometabolic disease; chemical uncoupling; mitochondria

DOI:  https://doi.org/10.1016/j.jbc.2024.105702
Redox Biol. 2024 Jan 27. pii: S2213-2317(24)00023-5. [Epub ahead of print]70 103047

Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions.

Caio Tabata Fukushima, Ian-Shika Dancil, Hannah Clary, Nidhi Shah, Sergiy M Nadtochiy, Paul S Brookes.

  Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90 % of ROS generation is from reverse electron transfer (RET) at the Q site of respiratory complex I (Cx-I). Together, these observations suggest Cx-I RET is the source of pathologic ROS in reperfusion injury. However, numerous factors present in early reperfusion may impact Cx-I RET, including: (i) High [NADH]; (ii) High [lactate]; (iii) Mildly acidic pH; (iv) Defined ATP/ADP ratios; (v) Presence of the nucleosides adenosine and inosine; and (vi) Defined free [Ca2+]. Herein, experiments with mouse cardiac mitochondria revealed that under simulated early reperfusion conditions including these factors, total mitochondrial ROS generation was only 56 ± 17 % of that seen with succinate alone (mean ± 95 % confidence intervals). Of this ROS, only 52 ± 20 % was assignable to Cx-I RET. A further 14 ± 7 % could be assigned to complex III, with the remainder (34 ± 11 %) likely originating from other ROS sources upstream of the Cx-I Q site. Together, these data suggest the relative contribution of Cx-I RET ROS to reperfusion injury may be overestimated, and other ROS sources may contribute a significant fraction of ROS in early reperfusion.

Keywords:  Complex-I; Ischemia; Mitochondria; Reactive oxygen species; Reperfusion; Reverse electron transfer

DOI:  https://doi.org/10.1016/j.redox.2024.103047