bims-mimcad 2024-01-07 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024‒01‒07
fifteen papers selected by
Henver Brunetta, University of Guelph

IKKβ stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy.
3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.
CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.
Mitochondrial density in skeletal and cardiac muscle.
Consuming a Linoleate-Rich Diet Increases Levels of Tetralinoleoyl Cardiolipin in Mouse Liver and Alters Hepatic Mitochondrial Respiration.
Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.
Mitochondria-derived reactive oxygen species are the likely primary trigger of mitochondrial retrograde signaling in Arabidopsis.
Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake.
Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
The biology of mitochondrial carrier homolog 2.
Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2.
Postnatal growth restriction alters myocardial mitochondrial energetics in mice.

Cardiovasc Res. 2024 Jan 02. pii: cvad145. [Epub ahead of print]

IKKβ stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy.

Matthew Guberman, Rimpy Dhingra, Jenna Cross, Victoria Margulets, Hongying Gang, Inna Rabinovich-Nikitin, Lorrie A Kirshenbaum.

  AIMS: The mitochondrial dynamics protein Mitofusin 2 (MFN2) coordinates critical cellular processes including mitochondrial bioenergetics, quality control, and cell viability. The NF-κB kinase IKKβ suppresses mitochondrial injury in doxorubicin cardiomyopathy, but the underlying mechanism is undefined.METHODS AND RESULTS: Herein, we identify a novel signalling axis that functionally connects IKKβ and doxorubicin cardiomyopathy to a mechanism that impinges upon the proteasomal stabilization of MFN2. In contrast to vehicle-treated cells, MFN2 was highly ubiquitinated and rapidly degraded by the proteasomal-regulated pathway in cardiac myocytes treated with doxorubicin. The loss of MFN2 activity resulted in mitochondrial perturbations, including increased reactive oxygen species (ROS) production, impaired respiration, and necrotic cell death. Interestingly, doxorubicin-induced degradation of MFN2 and mitochondrial-regulated cell death were contingent upon IKKβ kinase activity. Notably, immunoprecipitation and proximity ligation assays revealed that IKKβ interacted with MFN2 suggesting that MFN2 may be a phosphorylation target of IKKβ. To explore this possibility, mass spectrometry analysis identified a novel MFN2 phospho-acceptor site at serine 53 that was phosphorylated by wild-type IKKβ but not by a kinase-inactive mutant IKKβK-M. Based on these findings, we reasoned that IKKβ-mediated phosphorylation of serine 53 may influence MFN2 protein stability. Consistent with this view, an IKKβ-phosphomimetic MFN2 (MFN2S53D) was resistant to proteasomal degradation induced by doxorubicin whereas wild-type MFN2 and IKKβ-phosphorylation defective MFN2 mutant (MFNS53A) were readily degraded in cardiac myocytes treated with doxorubicin. Concordantly, gain of function of IKKβ or MFN2S53D suppressed doxorubicin-induced mitochondrial injury and cell death.
CONCLUSIONS: The findings of this study reveal a novel survival pathway for IKKβ that is mutually dependent upon and obligatory linked to the phosphorylation and stabilization of the mitochondrial dynamics protein MFN2.

Keywords:  Cardiac myocytes; Cell death; Doxorubicin; IKKβ; MFN2; Mitochondria

DOI:  https://doi.org/10.1093/cvr/cvad145
bioRxiv. 2023 Dec 14. pii: 2023.11.13.566502. [Epub ahead of print]

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.

Estevão Scudese, Zer Vue, Prassana Katti, Andrea Marshall, Larry Vang, Edgar Garza López, Kit Neikirk, Dominique Stephens, Duane D Hall, Rahmati Rostami, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine Wanjalla, Aaron Whiteside, Clintoria Williams, Steven M Damo, Jennifer A Gaddy, Annet Kirabo, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Vernat Exil, Bret C Mobley, Antentor Hinton.

Sarcopenia is an age-related loss of skeletal muscle, characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although mitochondrial aging is associated with decreased mitochondrial capacity, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging still requires further elucidation. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern these changes remain unclear. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. We found that mitochondria became less complex with age. Specifically, mitochondria lost surface area, complexity, and perimeter, indicating age-related declines in ATP synthesis and interaction capacity. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), which we show is required for mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved with Marf, the MFN2 ortholog in Drosophila , as Marf knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusins.

DOI: https://doi.org/10.1101/2023.11.13.566502
Am J Physiol Endocrinol Metab. 2024 Jan 03.

Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.

Hiroshi Kumagai, Su-Jeong Kim, Brendan Miller, Toshiharu Natsume, Junxiang Wan, Michi Emma Kumagai, Ricardo Ramirez Ii, Shin Hyung Lee, Ayaka Sato, Hemal H Mehta, Kelvin Yen, Pinchas Cohen.

  MOTS-c, a mitochondrial microprotein, has been described as a novel regulator of glucose and lipid metabolism. In addition to its role as a metabolic regulator, MOTS-c prevents skeletal muscle atrophy in high-fat-fed mice. Here, we examined the preventive effect of MOTS-c on skeletal muscle mass using an immobilization-induced muscle atrophy model and explored its underlying mechanisms. Male C57BL/6J mice (10-week-old) were randomly assigned to one of the three experimental groups: non-immobilization control group (sterilized water injection), immobilization control group (sterilized water injection), and immobilization and MOTS-c treated group (15 mg/kg/day MOTS-c injection). We used casting tape for the immobilization experiment. After eight days of the experimental period, skeletal muscle samples were collected and used for the Western blotting, RNA sequencing, lipid, and collagen assays. Immobilization reduced ~15% of muscle mass, while MOTS-c treatment attenuated muscle loss with only a 5% reduction. MOTS-c treatment also normalized phospho-AKT, phospho-FOXO1, and phospho-FOXO3a expression levels, and reduced circulating inflammatory cytokines, such as interleukin-1b (IL-1β), interleukin-6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1), in immobilized mice. An unbiased RNA sequencing and its downstream analyses demonstrated that MOTS-c modified adipogenic-modulating gene expression within the peroxisome proliferator-activated receptors (PPARs) pathway. Supporting this observation, muscle fatty acid levels were lower in the MOTS-c treated group than in the casted-controls. These results suggest that MOTS-c treatment inhibits skeletal muscle lipid infiltration by regulating adipogenesis-related genes and prevents immobilization-induced muscle atrophy.

Keywords:  MOTS-c; Mitochondrial microprotein; immobilization; muscle atrophy; myosteatosis

DOI:  https://doi.org/10.1152/ajpendo.00285.2023
Cell Rep. 2023 Dec 28. pii: S2211-1247(23)01637-6. [Epub ahead of print]43(1): 113626

CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.

Jin Ma, Ping-Yuan Wang, Jie Zhuang, Annie Y Son, Alexander K Karius, Abu Mohammad Syed, Masahiro Nishi, Zhichao Wu, Mateus P Mori, Young-Chae Kim, Paul M Hwang.

  Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.

Keywords:  CHCHD4; CP: Immunology; MyoD; TRIAP1; VDAC; cardiolipin; exercise adaptation; innate immune signaling; mitochondria; mtDNA; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2023.113626
Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00118-6. [Epub ahead of print]75 101838

Mitochondrial density in skeletal and cardiac muscle.

D Pesta.

Kubat et al. provide a review on the role Mitochondrial density in skeletal and cardiac muscle of mitochondrial dysfunction in muscle atrophy. They stress mitochondria's pivotal function, citing a 52 % density in skeletal muscle. However, the reference to Park et al.'s work misinterprets their findings. Park et al. report citrate synthase (CS) activity, indicating mitochondrial density as 222 ± 13 μmol.min-1.mg-1 for cardiac muscle and 115 ± 2 μmol.min-1.mg-1 for skeletal muscle. Thus, the authors should clarify that skeletal muscle density is approximately 52 % of cardiac muscle, not an absolute 52 %. Mitochondrial volume density assessment, predominantly through TEM, establishes cardiomyocytes at 25-30 % and untrained skeletal muscle at 2-6 %, increasing to 11 % in trained athletes. However, this remains modest compared to myofibrils' 75 %-85 % of muscle fiber volume. Although the utility of CS activity is evident, TEM and other novel approaches such as three-dimensional focused ion beam scanning electron microscopy are likely superior for assessing mitochondrial volume density and morphology.

DOI: https://doi.org/10.1016/j.mito.2023.101838
J Nutr. 2023 Dec 29. pii: S0022-3166(23)72826-5. [Epub ahead of print]

Consuming a Linoleate-Rich Diet Increases Levels of Tetralinoleoyl Cardiolipin in Mouse Liver and Alters Hepatic Mitochondrial Respiration.

Connor A Mahler, Deena B Snoke, Rachel M Cole, Austin Angelotti, Genevieve C Sparagna, Kedryn K Baskin, Ai Ni, Martha A Belury.

  BACKGROUND: Hepatic mitochondrial dysfunction has been found to be a major cause of fat accumulation in the liver and individuals with fatty liver conditions have hepatic mitochondrial structural abnormalities and a switch in the side chain composition of the mitochondrial phospholipid, cardiolipin, from poly- to monounsaturated fatty acids. Linoleic acid (LA), an essential dietary fatty acid, has been shown to remodel nascent cardiolipin to its tetralinoleoylcardiolipin (L4CL, cardiolipin with four LA side chains) form which is integral for mitochondrial membrane structure and function to promote fatty acid oxidation. It is unknown, however, whether increasing LA in the diet can increase hepatic L4CL levels, improve mitochondrial respiration compared to a diet rich in monounsaturated and saturated fatty acids.OBJECTIVES: The main aim of this study was to test the ability of a diet fortified with LA-rich safflower oil (SO), vs. one fortified with lard (LD), to change levels of L4CL and mitochondrial respiration in the livers of mice.
METHODS: Twenty-four (9-week-old) C57 BL/J6 male mice were fed either the (SO) or (LD) diets for ∼ 100 days while food intake and body weight, fasting glucose and glucose tolerance tests were performed to determine any changes in glycemic control.
RESULTS: Livers from mice fed SO diet had higher relative levels of hepatic L4CL species compared to LD diet-fed mice (p-value: 0.004). Uncoupled mitochondria of mice fed the SO diet, vs. LD diet, had an increased baseline oxygen consumption rate (OCR) and succinate driven respiration (p-values:0.03 & 0.01). SO diet fed mice had increased LA content in all phospholipid classes compared to LD fed mice (p-values: <0.05).
CONCLUSIONS: Our findings reveal that maintaining or increasing hepatic L4CL may result in increased OCR in uncoupled hepatic mitochondria in healthy mice whereas higher OA content of CL reduced mitochondrial function shown by lower OCR in uncoupled mitochondria.

Keywords:  Cardiolipin; Linoleic acid; Liver; Mitochondrial function

DOI:  https://doi.org/10.1016/j.tjnut.2023.12.037
Nat Commun. 2024 Jan 02. 15(1): 168

Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.

Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.

Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.

DOI: https://doi.org/10.1038/s41467-023-44057-6
Mol Metab. 2023 Dec 30. pii: S2212-8778(23)00203-X. [Epub ahead of print]79 101869

Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.

Alena Akhmetshina, Valentina Bianco, Ivan Bradić, Melanie Korbelius, Anita Pirchheim, Katharina B Kuentzel, Thomas O Eichmann, Helga Hinteregger, Dagmar Kolb, Hansjoerg Habisch, Laura Liesinger, Tobias Madl, Wolfgang Sattler, Branislav Radović, Simon Sedej, Ruth Birner-Gruenberger, Nemanja Vujić, Dagmar Kratky.

  OBJECTIVE: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions.RESULTS: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal-/- SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal-/-SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal-/- muscle size due to the "fiber paradox". Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal-/- SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo.
CONCLUSION: We conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.

Keywords:  Energy metabolism; LAL; LAL deficiency; Lal-deficient mouse; Muscle proteomics

DOI:  https://doi.org/10.1016/j.molmet.2023.101869
Curr Biol. 2023 Dec 28. pii: S0960-9822(23)01660-3. [Epub ahead of print]

Mitochondria-derived reactive oxygen species are the likely primary trigger of mitochondrial retrograde signaling in Arabidopsis.

Kasim Khan, Huy Cuong Tran, Berivan Mansuroglu, Pinar Önsell, Stefano Buratti, Markus Schwarzländer, Alex Costa, Allan G Rasmusson, Olivier Van Aken.

  Besides their central function in respiration, plant mitochondria play a crucial role in maintaining cellular homeostasis during stress by providing "retrograde" feedback to the nucleus. Despite the growing understanding of this signaling network, the nature of the signals that initiate mitochondrial retrograde regulation (MRR) in plants remains unknown. Here, we investigated the dynamics and causative relationship of a wide range of mitochondria-related parameters for MRR, using a combination of Arabidopsis fluorescent protein biosensor lines, in vitro assays, and genetic and pharmacological approaches. We show that previously linked physiological parameters, including changes in cytosolic ATP, NADH/NAD+ ratio, cytosolic reactive oxygen species (ROS), pH, free Ca2+, and mitochondrial membrane potential, may often be correlated with-but are not the primary drivers of-MRR induction in plants. However, we demonstrate that the induced production of mitochondrial ROS is the likely primary trigger for MRR induction in Arabidopsis. Furthermore, we demonstrate that mitochondrial ROS-mediated signaling uses the ER-localized ANAC017-pathway to induce MRR response. Finally, our data suggest that mitochondrially generated ROS can induce MRR without substantially leaking into other cellular compartments such as the cytosol or ER lumen, as previously proposed. Overall, our results offer compelling evidence that mitochondrial ROS elevation is the likely trigger of MRR.

Keywords:  Arabidopsis; mitochondria; reactive oxygen species; retrograde signaling

DOI:  https://doi.org/10.1016/j.cub.2023.12.005
Nutr Metab (Lond). 2024 Jan 02. 21(1): 4

Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake.

Kay L H Wu, Chih-Wei Wu, Lee-Wei Chen, Hsiao-Huang Chang, Ching-Li Cheng, Cai-Yi Wu, Yu-Chi Lee, I-Chun Chen, Chun-Ying Hung, Wen-Chung Liu.

  Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

Keywords:  Adipose whitening; High fructose diet; Mitochondrial dynamics; Perivascular adipose tissue; Vascular reactivity

DOI:  https://doi.org/10.1186/s12986-023-00776-7
Nat Commun. 2024 Jan 02. 15(1): 45

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.

Anna Worthmann, Julius Ridder, Sharlaine Y L Piel, Ioannis Evangelakos, Melina Musfeldt, Hannah Voß, Marie O'Farrell, Alexander W Fischer, Sangeeta Adak, Monica Sundd, Hasibullah Siffeti, Friederike Haumann, Katja Kloth, Tatjana Bierhals, Markus Heine, Paul Pertzborn, Mira Pauly, Julia-Josefine Scholz, Suman Kundu, Marceline M Fuh, Axel Neu, Klaus Tödter, Maja Hempel, Uwe Knippschild, Clay F Semenkovich, Hartmut Schlüter, Joerg Heeren, Ludger Scheja, Christian Kubisch, Christian Schlein.

Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.

DOI: https://doi.org/10.1038/s41467-023-44364-y
Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00117-4. [Epub ahead of print]75 101837

The biology of mitochondrial carrier homolog 2.

Xiaohe Zheng, Binxiang Chu.

  The mitochondrial carrier system is in charge of small molecule transport between the mitochondria and the cytoplasm as well as being an integral portion of the core mitochondrial function. One member of the mitochondrial carrier family of proteins, mitochondrial carrier homolog 2 (MTCH2), is characterized as a critical mitochondrial outer membrane protein insertase participating in mitochondrial homeostasis. Accumulating evidence demonstrate that MTCH2 is integrally linked to cell death and mitochondrial metabolism, and its genetic alterations cause a variety of disease phenotypes, ranging from obesity, Alzheimer's disease, and tumor. To provide a comprehensive insight into the current understanding of MTCH2, we present a detailed description of the physiopathological functions of MTCH2, ranging from apoptosis, mitochondrial dynamics, and metabolic homeostasis regulation. Moreover, we summarized the impact of MTCH2 in human diseases, and highlighted tumors, to assess the role of MTCH2 mutations or variable expression on pathogenesis and target therapeutic options.

Keywords:  Apoptosis; Lipid metabolism; MTCH2; Mitochondria; Tumor

DOI:  https://doi.org/10.1016/j.mito.2023.101837
Annu Rev Biophys. 2024 Jan 02.

Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.

Arun Kumar Kondadi, Andreas S Reichert.

Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: (a) within an individual mitochondrion, (b) among mitochondria, and (c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-biophys-030822-020736
iScience. 2024 Jan 19. 27(1): 108590

Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2.

Kaiyi Zhang, Ning Xie, Huaqiong Ye, Jiakun Miao, Boce Xia, Yu Yang, Huanqi Peng, Shuang Xu, Tianwen Wu, Cong Tao, Jinxue Ruan, Yanfang Wang, Shulin Yang.

  Skeletal muscle is a highly plastic organ that adapts to different metabolic states or functional demands. This study explored the impact of permanent glucose restriction (GR) on skeletal muscle composition and metabolism. Using Glut4m mice with defective glucose transporter 4, we conducted multi-omics analyses at different ages and after low-intensity treadmill training. The oxidative fibers were significantly increased in Glut4m muscles. Mechanistically, GR activated AMPK pathway, promoting mitochondrial function and beneficial myokine expression, and facilitated slow fiber formation via CaMK2 pathway. Phosphorylation-activated Perm1 may synergize AMPK and CaMK2 signaling. Besides, MAPK and CDK kinases were also implicated in skeletal muscle protein phosphorylation during GR response. This study provides a comprehensive signaling network demonstrating how GR influences muscle fiber types and metabolic patterns. These insights offer valuable data for understanding oxidative fiber formation mechanisms and identifying clinical targets for metabolic diseases.

Keywords:  Comp; Genomics; Metabolomics; Omics; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2023.108590
Exp Physiol. 2024 Jan 05.

Postnatal growth restriction alters myocardial mitochondrial energetics in mice.

Joseph R Visker, Eric C Leszczynski, Austin G Wellette-Hunsucker, Ashley C McPeek, Melissa A Quinn, Seong Hyun Kim, Jason N Bazil, David P Ferguson.

  Postnatal growth restriction (PGR) can increase the risk of cardiovascular disease (CVD) potentially due to impairments in oxidative phosphorylation (OxPhos) within cardiomyocyte mitochondria. The purpose of this investigation was to determine if PGR impairs cardiac metabolism, specifically OxPhos. FVB (Friend Virus B-type) mice were fed a normal-protein (NP: 20% protein), or low-protein (LP: 8% protein) isocaloric diet 2 weeks before mating. LP dams produce ∼20% less milk, and pups nursed by LP dams experience reduced growth into adulthood as compared to pups nursed by NP dams. At birth (PN1), pups born to dams fed the NP diet were transferred to LP dams (PGR group) or a different NP dam (control group: CON). At weaning (PN21), all mice were fed the NP diet. At PN22 and PN80, mitochondria were isolated for respirometry (oxygen consumption rate, JO2${J_{{{\mathrm{O}}_{\mathrm{2}}}}}$ ) and fluorimetry (reactive oxygen species emission, JH2O2${J_{{{\mathrm{H}}_{\mathrm{2}}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) analysis measured as baseline respiration (LEAK) and with saturating ADP (OxPhos). Western blotting at PN22 and PN80 determined protein abundance of uncoupling protein 3, peroxiredoxin-6, voltage-dependent anion channel and adenine nucleotide translocator 1 to provide further insight into mitochondrial function. ANOVAs with the main effects of diet, sex and age with α-level of 0.05 was set a priori. Overall, PGR (7.8 ± 1.1) had significant (P = 0.01) reductions in respiratory control in complex I when compared to CON (8.9 ± 1.0). In general, our results show that PGR led to higher electron leakage in the form of free radical production and reactive oxygen species emission. No significant diet effects were found in protein abundance. The observed reduced respiratory control and increased ROS emission in PGR mice may increase risk for CVD in mice.

Keywords:  cardiovascular disease; development; growth restriction; mitochondrial function; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1113/EP091304