bims-mimead 2024-09-29 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2024‒09‒29
eighteen papers selected by
Rachel M. Handy, University of Guelph

Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis.
The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion.
Epigenome-proteome integration in aged skeletal muscle after exercise training.
Effects of thyroid hormones in skeletal muscle protein turnover.
Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation.
Circulating proteomic profiles in women with morbid obesity compared to normal-weight women.
NADPH oxidases in healthy white adipose tissue and in obesity: function, regulation, and clinical implications.
Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
High glucose induces DNA methyltransferase 1 dependent epigenetic reprogramming of the endothelial exosome proteome in type 2 diabetes.
Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.
Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.
Dysbiosis and Regulation of Gut Microbiota in Type 2 Diabetes Mellitus.
Cannabinoids Block Fat-induced Incretin Release via CB1-dependent and CB1-independent Pathways in Intestinal Epithelium.
Novel insights into the role of bisphenol A (BPA) in genomic instability.

Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]

Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.

N Moradi, V C Sanfrancesco, S Champsi, D A Hood.

Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.09.028
Geroscience. 2024 Sep 23.

Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.

Robert V Musci, Jordan D Fuqua, Frederick F Peelor, Hoang Van Michelle Nguyen, Arlan Richardson, Solbie Choi, Benjamin F Miller, Jonathan Wanagat.

  Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.

Keywords:  Aging; Deuterium oxide; Mitochondrial DNA; Mutation; Rats; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-024-01344-4
bioRxiv. 2024 Sep 13. pii: 2024.09.12.612761. [Epub ahead of print]

The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis.

Daniel J Pape, Kelly C Falls-Hubert, Ronald A Merrill, Adnan Ahmed, Qingwen Qian, Gavin R McGivney, Paulina Sobieralski, Adam J Rauckhorst, Ling Yang, Eric B Taylor.

Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and 13 C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.

DOI: https://doi.org/10.1101/2024.09.12.612761
Biochem Pharmacol. 2024 Sep 24. pii: S0006-2952(24)00558-6. [Epub ahead of print] 116558

The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion.

Gia Cac Chau, Ji Eun Lim, Kyeongwon Moon, In Su Kim, Sung Hee Um.

  Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1H-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared with those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and β-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, β-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via β-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.

Keywords:  AMPK; HI 129; Indole derivative; Insulin secretion; Pancreatic β cells; β-arrestin-1

DOI:  https://doi.org/10.1016/j.bcp.2024.116558
J Physiol. 2024 Sep 19.

Epigenome-proteome integration in aged skeletal muscle after exercise training.

Adam P Sharples.



Keywords:  DNA methylation; aged muscle; endurance training; epigenetics; exercise; high‐intensity interval training; methylome; omics; proteome; resistance training; skeletal muscle

DOI:  https://doi.org/10.1113/JP287235
J Basic Clin Physiol Pharmacol. 2024 Sep 20.

Effects of thyroid hormones in skeletal muscle protein turnover.

Annarita Nappi, Caterina Moriello, Maria Morgante, Ferdinando Fusco, Felice Crocetto, Caterina Miro.

  Thyroid hormones (THs) are critical regulators of muscle metabolism in both healthy and unhealthy conditions. Acting concurrently as powerful anabolic and catabolic factors, THs are endowed with a vital role in muscle mass maintenance. As a result, thyroid dysfunctions are the leading cause of a wide range of muscle pathologies, globally identified as myopathies. Whether muscle wasting is a common feature in patients with hyperthyroidism and is mainly caused by THs-dependent stimulation of muscle proteolysis, also muscle growth is often associated with hyperthyroid conditions, linked to THs-dependent stimulation of muscle protein synthesis. Noteworthy, also hypothyroid status negatively impacts on muscle physiology, causing muscle weakness and fatigue. Most of these symptoms are due to altered balance between muscle protein synthesis and breakdown. Thus, a comprehensive understanding of THs-dependent skeletal muscle protein turnover might facilitate the management of physical discomfort or weakness in conditions of thyroid disease. Herein, we describe the molecular mechanisms underlying the THs-dependent alteration of skeletal muscle structure and function associated with muscle atrophy and hypertrophy, thus providing new insights for targeted modulation of skeletal muscle dynamics.

Keywords:  skeletal muscle; skeletal muscle atrophy; skeletal muscle hypertrophy; thyroid hormones

DOI:  https://doi.org/10.1515/jbcpp-2024-0139
Diseases. 2024 Aug 23. pii: 195. [Epub ahead of print]12(9):

Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation.

Ginka Delcheva, Katya Stefanova, Teodora Stankova.

  Abnormalities in lipid homeostasis have been associated with many human diseases, and the interrelation between lipotoxicity and cellular dysfunction has received significant attention in the past two decades. Ceramides (Cers) are bioactive lipid molecules that serve as precursors of all complex sphingolipids. Besides their function as structural components in cell and mitochondrial membranes, Cers play a significant role as key mediators in cell metabolism and are involved in numerous cellular processes, such as proliferation, differentiation, inflammation, and induction of apoptosis. The accumulation of various ceramides in tissues causes metabolic and cellular disturbances. Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular diseases (CVDs). In humans, elevated plasma ceramide levels are associated with insulin resistance and impaired cardiovascular and metabolic health. In this review, we summarize the role of ceramides as key mediators of lipotoxicity in obesity, diabetes, cardiovascular diseases, and inflammation and their potential as a promising diagnostic tool.

Keywords:  cardiovascular diseases; ceramides; diabetes; inflammation; lipotoxicity

DOI:  https://doi.org/10.3390/diseases12090195
J Proteomics. 2024 Sep 21. pii: S1874-3919(24)00249-5. [Epub ahead of print]310 105317

Circulating proteomic profiles in women with morbid obesity compared to normal-weight women.

Laia Bertran, Elena Cristina Rusu, Maria Guirro, Carmen Aguilar, Teresa Auguet, Cristóbal Richart.

  In this study, we aimed to evaluate circulating proteomic levels in women with morbid obesity (MO) compared to normal-weight (NW) women. Moreover, we have compared the proteomic profile between women with metabolically healthy (MH) MO and those with type 2 diabetes mellitus (T2DM). The study included 66 normal-weight (NW) women and 129 women with MO (54 MH and 75 with T2DM). Blood samples were processed for proteomics, involving protein extraction, quantification, digestion with peptide labelling and Nano (liquid chromatography (LC)-(Orbitrap) coupled to mass/mass spectrometry (MS/MS) analysis. Statistical analyses were performed. We identified 257 proteins. Women with MO showed significantly increased levels of 35 proteins and decreased levels of 45 proteins compared to NW women. Enrichment analysis of metabolic pathways revealed significant findings. Women with MO have an altered proteomic profile compared to normal-weight women, involving proteins significantly related to chylomicron assembly, complement cascade, clotting pathways and the insulin growth factor system. Regarding women with MO and T2DM compared to MHMO women, the proteomic profile shows alterations in mostly the same pathways associated with obesity. These findings confirmed in previous reports can help us better understand the pathophysiology of obesity and associated diseases. SIGNIFICANCE: Women with morbid obesity (MO) exhibit substantial proteomic alterations compared to normal-weight (NW) women, involving 80 proteins. These alterations are linked to significant metabolic pathways, including chylomicron assembly, complement cascade, clotting pathways and the insulin growth factor system. Additionally, women with MO and type 2 diabetes mellitus (T2DM) compared to metabolically healthy MO women share similar proteomic changes than the first comparison. These findings enhance our understanding of the pathophysiology of obesity and associated diseases, offering potential targets for therapeutic intervention.

Keywords:  Metabolically healthy obesity; Morbid obesity; Proteomics; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.jprot.2024.105317
Obesity (Silver Spring). 2024 Oct;32(10): 1799-1811

NADPH oxidases in healthy white adipose tissue and in obesity: function, regulation, and clinical implications.

François R Jornayvaz, Karim Gariani, Emmanuel Somm, Vincent Jaquet, Karim Bouzakri, Ildiko Szanto.

Reactive oxygen species, when produced in a controlled manner, are physiological modulators of healthy white adipose tissue (WAT) expansion and metabolic function. By contrast, unbridled production of oxidants is associated with pathological WAT expansion and the establishment of metabolic dysfunctions, most notably insulin resistance and type 2 diabetes mellitus. NADPH oxidases (NOXs) produce oxidants in an orderly fashion and are present in adipocytes and in other diverse WAT-constituent cell types. Recent studies have established several links between aberrant NOX-derived oxidant production, adiposity, and metabolic homeostasis. The objective of this review is to highlight the physiological roles attributed to diverse NOX isoforms in healthy WAT and summarize current knowledge of the metabolic consequences related to perturbations in their adequate oxidant production. We detail WAT-related alterations in preclinical investigations conducted in NOX-deficient murine models. In addition, we review clinical studies that have employed NOX inhibitors and currently available data related to human NOX mutations in metabolic disturbances. Future investigations aimed at understanding the integration of NOX-derived oxidants in the regulation of the WAT cellular redox network are essential for designing successful redox-related precision therapies to curb obesity and attenuate obesity-associated metabolic pathologies.

DOI: https://doi.org/10.1002/oby.24113
FASEB J. 2024 Sep 30. 38(18): e70066

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.

  Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.

Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species

DOI:  https://doi.org/10.1096/fj.202400313R
Int J Biochem Cell Biol. 2024 Sep 19. pii: S1357-2725(24)00156-0. [Epub ahead of print]176 106664

High glucose induces DNA methyltransferase 1 dependent epigenetic reprogramming of the endothelial exosome proteome in type 2 diabetes.

Sampara Vasishta, Shruthi Ammankallu, Ganesha Poojary, Sarah Michael Gomes, Kailash Ganesh, Shashikiran Umakanth, Prashanth Adiga, Dinesh Upadhya, Thottethodi Subrahmanya Keshava Prasad, Manjunath B Joshi.

  In response to hyperglycemia, endothelial cells (ECs) release exosomes with altered protein content and contribute to paracrine signalling, subsequently leading to vascular dysfunction in type 2 diabetes (T2D). High glucose reprograms DNA methylation patterns in various cell/tissue types, including ECs, resulting in pathologically relevant changes in cellular and extracellular proteome. However, DNA methylation-based proteome reprogramming in endothelial exosomes and associated pathological implications in T2D are not known. Hence, in the present study, we used Human umbilical vein endothelial cells (HUVECs), High Fat Diet (HFD) induced diabetic mice (C57BL/6) and clinical models to understand epigenetic basis of exosome proteome regulation in T2D pathogenesis . Exosomes were isolated by size exclusion chromatography and subjected to tandem mass tag (TMT) labelled quantitative proteomics and bioinformatics analysis. Immunoblotting was performed to validate exosome protein signature in clinically characterized individuals with T2D. We observed ECs cultured in high glucose and aortic ECs from HFD mouse expressed elevated DNA methyltransferase1 (DNMT1) levels. Quantitative proteomics of exosomes isolated from ECs treated with high glucose and overexpressing DNMT1 showed significant alterations in both protein levels and post translational modifications which were aligned to T2D associated vascular functions. Based on ontology and gene-function-disease interaction analysis, differentially expressed exosome proteins such as Thrombospondin1, Pentraxin3 and Cystatin C related to vascular complications were significantly increased in HUVECs treated with high glucose and HFD animals and T2D individuals with higher levels of glycated hemoglobin. These proteins were reduced upon treatment with 5-Aza-2'-deoxycytidine. Our study shows epigenetic regulation of exosome proteome in T2D associated vascular complications.

Keywords:  DNA methylation; Endothelial cells; Exosomes; Quantitative Proteomics; Type 2 Diabetes

DOI:  https://doi.org/10.1016/j.biocel.2024.106664
Nat Commun. 2024 Sep 27. 15(1): 8274

Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.

Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.

A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.

DOI: https://doi.org/10.1038/s41467-024-52183-y
Biochem Pharmacol. 2024 Sep 20. pii: S0006-2952(24)00552-5. [Epub ahead of print]229 116552

Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.

Warisara Parichatikanond, Sudhir Pandey, Supachoke Mangmool.

  Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9-39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9-39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.

Keywords:  Cardioprotection; Exendin-4; GLP-1 receptor; High glucose; Mitochondrial dysfunction; mTOR

DOI:  https://doi.org/10.1016/j.bcp.2024.116552
J Lipid Res. 2024 Sep 18. pii: S0022-2275(24)00148-2. [Epub ahead of print] 100643

Setting the curve: the biophysical properties of lipids in mitochondrial form and function.

Kailash Venkatraman, Christopher T Lee, Itay Budin.

  Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane (IMM), highly-curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane (OMM) is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, inter-organelle contacts, fission and fusion dynamics and metabolite transport. While the lipid composition of both the IMM and OMM have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes, ether lipids and sterols, with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.

Keywords:  Cardiolipin; Curvature; Mitochondria; Phospholipids; Plasmalogens; Sterols

DOI:  https://doi.org/10.1016/j.jlr.2024.100643
NAR Genom Bioinform. 2023 Dec;5(4): lqad107

Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.

Dmitriy Leyfer, Jessica L Fetterman.

Mitochondrial diseases are the result of pathogenic variants in genes involved in the diverse functions of the mitochondrion. A comprehensive list of mitochondrial genes is needed to improve gene prioritization in the diagnosis of mitochondrial diseases and development of therapeutics that modulate mitochondrial function. MitoCarta is an experimentally derived catalog of proteins localized to mitochondria. We sought to expand this list of mitochondrial proteins to identify proteins that may not be localized to the mitochondria yet perform important mitochondrial functions. We used a computational approach to assign statistical significance to the overlap between STRING database gene network neighborhoods and MitoCarta proteins. Using a data-driven stringent significance threshold, 2059 proteins that were not located in MitoCarta were identified, which we termed mitochondrial proximal (MitoProximal) proteins. We identified all of the oxidative phosphorylation complex subunits and 90% of 149 genes that contain confirmed oxidative phosphorylation disease causal variants, lending validation to our methodology. Among the MitoProximal proteins, 134 are annotated to be localized to mitochondria but are not in the MitoCarta 3.0 database. We extend MitoCarta nearly 3-fold, generating a more comprehensive list of mitochondrial genes, a resource to facilitate the identification of pathogenic variants in mitochondrial and metabolic diseases.

DOI: https://doi.org/10.1093/nargab/lqad107
Curr Pharm Biotechnol. 2024 Sep 25.

Dysbiosis and Regulation of Gut Microbiota in Type 2 Diabetes Mellitus.

Minakshi, Hemlata Kumari, Shaurya Prakash, Antresh Kumar.

  Type 2 diabetes mellitus is a serious metabolic disease having a high growth rate and becoming a global threat. An unhealthy lifestyle, food intake, and genetic susceptibility are the major factors responsible for this metabolic disorder. This disease results in hyperlipidemia, hyperglycemia, glucose intolerance, restricted insulin synthesis, and insulin resistance. Despite a variety of treatments currently available, cases of diabetes and resulting complications are on the rise. One promising approach to diabetes focuses on gut microflora and their associated metabolites. Gut microbiota has attracted widespread attention due to its crucial role in disease pathophysiology. This study explores the dysbiosis in the human gut microflora in Type 2 Diabetes Mellitus and how the gut microbiota influences metabolites related to T2DM. It also sheds light on early identification and targeted intervention for this. Understanding these mechanisms could potentially lead to more effective strategies for managing and preventing T2DM. The findings of our literature study are that gut microbiota can serve as biomarkers for early disease detection. Finally, we also highlight gut microecological therapeutic strategies focused on shaping the gut flora to emphasize the improvement of T2DM progression.

Keywords:  Aromatic amino acids.; Diabetes; Gut microbiota; Short-chain fatty acids; Trimethylamine N-oxide; dysbiosis; endotoxemia

DOI:  https://doi.org/10.2174/0113892010318580240910061534
Gastro Hep Adv. 2024 ;3(7): 931-941

Cannabinoids Block Fat-induced Incretin Release via CB1-dependent and CB1-independent Pathways in Intestinal Epithelium.

Pedro Antonio Perez, Mark Benjamin Wiley, Alexandros Makriyannis, Nicholas Vincent DiPatrizio.

  Background and Aims: Glucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB1R) are expressed in these cell subpopulations; however, roles for CB1Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB1Rs control fat-induced incretin secretion.Methods: We treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1-/-) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9 tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545. Circulating incretin levels were measured in plasma.
Results: Oral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB1+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by coadministration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not GLP1, in IntCB1-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells.
Conclusion: These results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms.

Keywords:  Cannabinoid; Incretin; Intestinal Epithelium

DOI:  https://doi.org/10.1016/j.gastha.2024.07.006
NAR Cancer. 2024 Sep;6(3): zcae038

Novel insights into the role of bisphenol A (BPA) in genomic instability.

Anastasia Hale, George-Lucian Moldovan.

Bisphenol A (BPA) is a phenolic chemical that has been used for over 50 years in the manufacturing of polycarbonate and polyvinyl chloride plastics, and it is one of the highest volume chemicals produced worldwide. Because BPA can bind to and activate estrogen receptors, studies have mainly focused on the effect of BPA in disrupting the human endocrine and reproductive systems. However, BPA also plays a role in promoting genomic instability and has been associated with initiating carcinogenesis. For example, it has been recently shown that exposure to BPA promotes the formation of single stranded DNA gaps, which may be associated with increased genomic instability. In this review, we outline the mechanisms by which BPA works to promote genomic instability including chromosomal instability, DNA adduct formation, ROS production, and estrogen receptor (ER) activation. Moreover, we define the ways in which BPA promotes both carcinogenesis and resistance to chemotherapy, and we provide critical insights into future directions and outstanding questions in the field.

DOI: https://doi.org/10.1093/narcan/zcae038