bims-mimcad 2024-04-07 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–04–07
seven papers selected by
Henver Brunetta, University of Guelph

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity.
Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.
Grb7 ablation in mice improved glycemic control, enhanced insulin signaling and increased abdominal fat mass in females.
The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.
The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.

Sci Adv. 2024 Apr 05. 10(14): eadl0389

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.

Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.

The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.

DOI: https://doi.org/10.1126/sciadv.adl0389
Cell Metab. 2024 Apr 02. pii: S1550-4131(24)00081-0. [Epub ahead of print]36(4): 745-761.e5

Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity.

Max C Petersen, Gordon I Smith, Hector H Palacios, Sarah S Farabi, Mihoko Yoshino, Jun Yoshino, Kevin Cho, Victor G Davila-Roman, Mahalakshmi Shankaran, Ruteja A Barve, Jinsheng Yu, Jennifer H Stern, Bruce W Patterson, Marc K Hellerstein, Gerald I Shulman, Gary J Patti, Samuel Klein.

  There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).

Keywords:  adipose tissue; beta cell function; insulin resistance; insulin sensitivity; metabolically healthy obesity; obesity; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.03.002
J Physiol. 2024 Apr 02.

Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.

Hailey A Parry, T Bradley Willingham, Kevin A Giordano, Yuho Kim, Shureed Qazi, Jay R Knutson, Christian A Combs, Brian Glancy.

  Mitochondria within skeletal muscle cells are located either between the muscle contractile apparatus (interfibrillar mitochondria, IFM) or beneath the cell membrane (subsarcolemmal mitochondria, SSM), with several structural and functional differences reported between IFM and SSM. However, recent 3D imaging studies demonstrate that mitochondria are particularly concentrated in the proximity of capillaries embedded in sarcolemmal grooves rather than in proximity to the sarcolemma itself (paravascular mitochondria, PVM). To evaluate the impact of capillary vs. sarcolemmal proximity, we compared the structure and function of skeletal muscle mitochondria located either lateral to embedded capillaries (PVM), adjacent to the sarcolemma but not in PVM pools (SSM) or interspersed between sarcomeres (IFM). Mitochondrial morphology and interactions were assessed by 3D electron microscopy coupled with machine learning segmentation, whereas mitochondrial energy conversion was assessed by two-photon microscopy of mitochondrial membrane potential, content, calcium, NADH redox and flux in live, intact cells. Structurally, although PVM and SSM were similarly larger than IFM, PVM were larger, rounder and had more physical connections to neighbouring mitochondria compared to both IFM and SSM. Functionally, PVM had similar or greater basal NADH flux compared to SSM and IFM, respectively, despite a more oxidized NADH pool and a greater membrane potential, signifying a greater activation of the electron transport chain in PVM. Together, these data indicate that proximity to capillaries has a greater impact on resting mitochondrial energy conversion and distribution in skeletal muscle than the sarcolemma alone. KEY POINTS: Capillaries have a greater impact on mitochondrial energy conversion in skeletal muscle than the sarcolemma. Paravascular mitochondria are larger, and the outer mitochondrial membrane is more connected with neighbouring mitochondria. Interfibrillar mitochondria are longer and have greater contact sites with other organelles (i.e. sarcoplasmic reticulum and lipid droplets). Paravascular mitochondria have greater activation of oxidative phosphorylation than interfibrillar mitochondria at rest, although this is not regulated by calcium.

Keywords:  energy function; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP286246
Endocrinology. 2024 Apr 05. pii: bqae045. [Epub ahead of print]

Grb7 ablation in mice improved glycemic control, enhanced insulin signaling and increased abdominal fat mass in females.

Anke Vermehren-Schmaedick, Sonali Joshi, Wendy Wagoner, Mason A Norgard, William Packwood, Parham Diba, Heike Mendez, Lev M Fedorov, Shauna Rakshe, Byung Park, Daniel L Marks, Aaron Grossberg, Shiuh-Wen Luoh.

   OBJECTIVE: Growth Factor Receptor Bound Protein 7 (GRB7) is a multi-domain signaling adaptor. Members of the Grb7/10/14 family, specifically Gbrb10/14, have important roles in metabolism. We ablated the Grb7 gene in mice to examine its metabolic function.
METHODS: Global ablation of Grb7 in FVB/NJ mice was generated. Growth, organ weight, food intake, and glucose homeostasis were measured. Insulin signaling was examined by Western blotting. Fat and lean body mass was measured by Nuclear Magnetic Resonance, and body composition after fasting or high fat diet was assessed. Energy expenditure was measured by indirect calorimetry. Expression of adiposity and lipid metabolism genes was measured by qPCR.
RESULTS: Grb7-null mice were viable, fertile and without obvious phenotype. Grb7 ablation improved glycemic control and displayed sensitization to insulin signaling in the liver. Grb7-null females but not males had increased gonadal white adipose tissue mass. Following a 12-week high fat diet, Grb7-null female mice gained fat body mass and developed relative insulin resistance. With fasting, there was less decrease in fat body mass in Grb7-null female mice. Female mice with Grb7 ablation had increased baseline food intake, less energy expenditure and displayed a decrease in the expression of lipolysis and adipose browning genes in gonadal white adipose tissue by transcript and protein analysis.
CONCLUSIONS: Our study suggests that Grb7 is a negative regulator of glycemic control. Our results reveal a role for Grb7 in female mice in the regulation of the visceral adipose tissue mass, a powerful predictor of metabolic dysfunction in obesity.

Keywords:   Grb7 ; adipose tissue; browning; glycemic control

DOI:  https://doi.org/10.1210/endocr/bqae045
EMBO Rep. 2024 Apr 02.

The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.

Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.

  Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.

Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import

DOI:  https://doi.org/10.1038/s44319-024-00113-w
Nat Commun. 2024 Mar 30. 15(1): 2779

TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.

Cheoljun Choi, Yujin L Jeong, Koung-Min Park, Minji Kim, Sangseob Kim, Honghyun Jo, Sumin Lee, Heeseong Kim, Garam Choi, Yoon Ha Choi, Je Kyung Seong, Sik Namgoong, Yeonseok Chung, Young-Suk Jung, James G Granneman, Young-Min Hyun, Jong Kyoung Kim, Yun-Hee Lee.

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

DOI: https://doi.org/10.1038/s41467-024-47108-8
Acta Physiol (Oxf). 2024 Apr 05. e14143

The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.

Kristina Žuna, Tatyana Tyschuk, Taraneh Beikbaghban, Felix Sternberg, Jürgen Kreiter, Elena E Pohl.

   AIMS: Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2-oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons.
METHODS: The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance (Gm) of planar lipid bilayers. OGC-mediated substrate transport was measured in proteoliposomes using 14C-malate.
RESULTS: OGC increases proton Gm only in the presence of natural (long-chain fatty acids, FA) or chemical (2,4-dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism.
CONCLUSION: OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.

Keywords:  SLC25A11; long‐chain fatty acids; mitochondrial transport; planar bilayer membranes; proton transport; total membrane conductance

DOI:  https://doi.org/10.1111/apha.14143