bims-mifefi 2024-02-04 papers

bims-mifefi

Biomed News

on Mitochondria and female physiology

Issue of 2024‒02‒04
fourteen papers selected by
Kayla Vandiver, East Carolina University

Molecular Effects of Vitamin-D and PUFAs metabolism in Skeletal Muscle combating Type-II Diabetes mellitus.
Mitochondrial involvement in sarcopenia.
The involvement of the mitochondrial membrane in drug delivery.
Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications.
The role of autophagy in insulin resistance and glucolipid metabolism and potential use of autophagy modulating natural products in the treatment of type 2 diabetes mellitus.
Long-term iron supplementation combined with vitamin B6 enhances maximal oxygen uptake and promotes skeletal muscle-specific mitochondrial biogenesis in rats.
Discovery of potential biomarkers for osteoporosis using LC/GC-MS metabolomic methods.
Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human iPSC-derived neural models.
The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
Synthesis of a Novel Gold(I) Complex and Evaluation of Its Anticancer Properties in Breast Cancer Cells.
Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3.
Estrogens, Adipose Tissues, and Environmental Exposures Influence Obesity and Diabetes Across the Lifecycle.
Lifespan effects of muscle-specific androgen receptor overexpression on body composition of male and female rats.
The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.

Gene. 2024 Jan 31. pii: S0378-1119(24)00097-0. [Epub ahead of print] 148216

Molecular Effects of Vitamin-D and PUFAs metabolism in Skeletal Muscle combating Type-II Diabetes mellitus.

Rajan Logesh, Balaji Hari, Kumarappan Chidambaram, Niranjan Das.

  Multiple post-receptor intracellular alterations such as impaired glucose transfer, glucose phosphorylation, decreased glucose oxidation, and glycogen production contribute to insulin resistance (IR) in skeletal muscle, manifested by diminished insulin-stimulated glucose uptake. Type-2 diabetes mellites (T2DM) has caused by IR, which is also seen in obese patients and those with metabolic syndrome. The Vitamin-D receptor (VDR) and poly unsaturated fatty acids (PUFAs) roles in skeletal muscle growth, shapes, and function for combating type-2 diabetes have been clarified throughout this research. VDR and PUFAs appears to show a variety of effects on skeletal muscle, in addition it shows a promising role on bone and mineral homeostasis. Individuals having T2DM are reported to suffer from severe muscular weakness and alterations in shape of the muscle. Several studies have investigated the effect on VDR on muscular strength and mass, which leads to Vitamin-D deficiency (VDD) in individuals, in which most commonly seen in elderly. VDR has been shown to affect skeletal cellular proliferation, intracellular calcium handling, as well as genomic activity in a variety of different ways such as muscle metabolism, insulin sensitivity, which is the major characteristic pathogenesis for IR in combating T2DM. The identified VDR gene polymorphisms are ApaI, TaqI, FokI, and BsmI that are associated with T2DM. This review collates informations on the mechanisms by which VDR activation takes place in skeletal muscles. Despite the significant breakthroughs made in recent decades, various studies show that IR affects VDR and PUFAs metabolism in skeletal muscle. Therefore, this review collates the data to show the role of VDR and PUFAs in the skeletal muscles to combat T2DM.

Keywords:  Insulin Resistance; Polyunsaturated Fatty acids; Skeletal muscles; Type 2 Diabetes Mellitus; Vitamin D receptor

DOI:  https://doi.org/10.1016/j.gene.2024.148216
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 Biomater. 2024 Jan 25. pii: S1742-7061(24)00039-4. [Epub ahead of print]

The involvement of the mitochondrial membrane in drug delivery.

Yinghui Huang, Wenhui Ji, Jiaxin Zhang, Ze Huang, Aixiang Ding, Hua Bai, Bo Peng, Kai Huang, Wei Du, Tingting Zhao, Lin Li.

  Treatment effectiveness and biosafety are critical for disease therapy. Bio-membrane modification facilitates the homologous targeting of drugs in vivo by exploiting unique antibodies or antigens, thereby enhancing therapeutic efficacy while ensuring biosafety. To further enhance the precision of disease treatment, future research should shift focus from targeted cellular delivery to targeted subcellular delivery. As the cellular powerhouses, mitochondria play an indispensable role in cell growth and regulation and are closely involved in many diseases (e.g., cancer, cardiovascular, and neurodegenerative diseases). The double-layer membrane wrapped on the surface of mitochondria not only maintains the stability of their internal environment but also plays a crucial role in fundamental biological processes, such as energy generation, metabolite transport, and information communication. A growing body of evidence suggests that various diseases are tightly related to mitochondrial imbalance. Moreover, mitochondria-targeted strategies hold great potential to decrease therapeutic threshold dosage, minimize side effects, and promote the development of precision medicine. Herein, we introduce the structure and function of mitochondrial membranes, summarize and discuss the important role of mitochondrial membrane-targeting materials in disease diagnosis/treatment, and expound the advantages of mitochondrial membrane-assisted drug delivery for disease diagnosis, treatment, and biosafety. This review helps readers understand mitochondria-targeted therapies and promotes the application of mitochondrial membranes in drug delivery. STATEMENT OF SIGNIFICANCE: Bio-membrane modification facilitates the homologous targeting of drugs in vivo by exploiting unique antibodies or antigens, thereby enhancing therapeutic efficacy while ensuring biosafety. Compared to cell-targeted treatment, targeting of mitochondria for drug delivery offers higher efficiency and improved biosafety and will promote the development of precision medicine. As a natural material, the mitochondrial membrane exhibits excellent biocompatibility and can serve as a carrier for mitochondria-targeted delivery. This review provides an overview of the structure and function of mitochondrial membranes and explores the potential benefits of utilizing mitochondrial membrane-assisted drug delivery for disease treatment and biosafety. The aim of this review is to enhance readers' comprehension of mitochondrial targeted therapy and to advance the utilization of mitochondrial membrane in drug delivery.

Keywords:  disease treatment; drug delivery; mitochondrial membrane; mitochondrial targeting; structure and function

DOI:  https://doi.org/10.1016/j.actbio.2024.01.027
Front Endocrinol (Lausanne). 2023 ;14 1268308

Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications.

Naila Rabbani, Paul J Thornalley.

  Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.

Keywords:  diabetes; glucose metabolism; glucotoxicity; hyperglycermia; insulin resistance; vascular complications

DOI:  https://doi.org/10.3389/fendo.2023.1268308
Diabetes Metab Res Rev. 2024 Jan;40(1): e3762

The role of autophagy in insulin resistance and glucolipid metabolism and potential use of autophagy modulating natural products in the treatment of type 2 diabetes mellitus.

Xiaoxue Yang, Wenwen Ding, Ziyi Chen, Kaiyi Lai, Ying Liu.

  Type 2 diabetes mellitus (T2DM) is a severe, long-term condition characterised by disruptions in glucolipid and energy metabolism. Autophagy, a fundamental cellular process, serves as a guardian of cellular health by recycling and renewing cellular components. To gain a comprehensive understanding of the vital role that autophagy plays in T2DM, we conducted an extensive search for high-quality publications across databases such as Web of Science, PubMed, Google Scholar, and SciFinder and used keywords like 'autophagy', 'insulin resistance', and 'type 2 diabetes mellitus', both individually and in combinations. A large body of evidence underscores the significance of activating autophagy in alleviating T2DM symptoms. An enhanced autophagic activity, either by activating the adenosine monophosphate-activated protein kinase and sirtuin-1 signalling pathways or inhibiting the mechanistic target of rapamycin complex 1 signalling pathway, can effectively improve insulin resistance and balance glucolipid metabolism in key tissues like the hypothalamus, skeletal muscle, liver, and adipose tissue. Furthermore, autophagy can increase β-cell mass and functionality in the pancreas. This review provides a narrative summary of autophagy regulation with an emphasis on the intricate connection between autophagy and T2DM symptoms. It also discusses the therapeutic potentials of natural products with autophagy activation properties for the treatment of T2DM conditions. Our findings suggest that autophagy activation represents an innovative approach of treating T2DM.

Keywords:  autophagy; cell metabolism; insulin resistance; natural products; type 2 diabetes mellitus

DOI:  https://doi.org/10.1002/dmrr.3762
Front Nutr. 2023 ;10 1335187

Long-term iron supplementation combined with vitamin B6 enhances maximal oxygen uptake and promotes skeletal muscle-specific mitochondrial biogenesis in rats.

Lei Zhou, Soroosh Mozaffaritabar, Attila Kolonics, Takuji Kawamura, Atsuko Koike, Johanna Kéringer, Yaodong Gu, Roman Karabanov, Zsolt Radák.

  Introduction: Iron is an essential micronutrient that plays a crucial role in various biological processes. Previous studies have shown that iron supplementation is related to exercise performance and endurance capacity improvements. However, the underlying mechanisms responsible for these effects are not well understood. Recent studies have suggested the beneficial impact of iron supplementation on mitochondrial function and its ability to rescue mitochondrial function under adverse stress in vitro and rodents. Based on current knowledge, our study aimed to investigate whether the changes in exercise performance resulting from iron supplementation are associated with its effect on mitochondrial function.Methods: In this study, we orally administered an iron-based supplement to rats for 30 consecutive days at a dosage of 0.66 mg iron/kg body weight and vitamin B6 at a dosage of 0.46 mg/kg.
Results: Our findings reveal that long-term iron supplementation, in combination with vitamin B6, led to less body weight gained and increased VO2 max in rats. Besides, the treatment substantially increased Complex I- and Complex II-driven ATP production in intact mitochondria isolated from gastrocnemius and cerebellum. However, the treatment did not change basal and succinate-induced ROS production in mitochondria from the cerebellum and skeletal muscle. Furthermore, the iron intervention significantly upregulated several skeletal muscle mitochondrial biogenesis and metabolism-related biomarkers, including PGC-1α, SIRT1, NRF-2, SDHA, HSL, MTOR, and LON-P. However, it did not affect the muscular protein expression of SIRT3, FNDC5, LDH, FIS1, MFN1, eNOS, and nNOS. Interestingly, the iron intervention did not exert similar effects on the hippocampus of rats.
Discussion: In conclusion, our study demonstrates that long-term iron supplementation, in combination with vitamin B6, increases VO2 max, possibly through its positive role in regulating skeletal muscle-specific mitochondrial biogenesis and energy production in rats.

Keywords:  VO2 max; exercise performance; iron supplementation; mitochondrial biogenesis; skeletal muscle; vitamin B6

DOI:  https://doi.org/10.3389/fnut.2023.1335187
Front Endocrinol (Lausanne). 2023 ;14 1332216

Discovery of potential biomarkers for osteoporosis using LC/GC-MS metabolomic methods.

Yahui Wu, Chunhua Yuan, Peipei Han, Jiangling Guo, Yue Wang, Cheng Chen, Chuanjun Huang, Kai Zheng, Yiqiong Qi, Jiajin Li, Zhengjie Xue, Fanchen Lu, Dongyu Liang, Jing Gao, Xingyan Li, Qi Guo.

  Purpose: For early diagnosis of osteoporosis (OP), plasma metabolomics of OP was studied by untargeted LC/GC-MS in a Chinese elderly population to find possible diagnostic biomarkers.Methods: A total of 379 Chinese community-dwelling older adults aged ≥65 years were recruited for this study. The BMD of the calcaneus was measured using quantitative ultrasound (QUS), and a T value ≤-2.5 was defined as OP. Twenty-nine men and 47 women with OP were screened, and 29 men and 36 women were matched according to age and BMI as normal controls using propensity matching. Plasma from these participants was first analyzed by untargeted LC/GC-MS, followed by FC and P values to screen for differential metabolites and heatmaps and box plots to differentiate metabolites between groups. Finally, metabolic pathway enrichment analysis of differential metabolites was performed based on KEGG, and pathways with P ≤ 0.05 were selected as enrichment pathways.
Results: We screened metabolites with FC>1.2 or FC<1/1.2 and P<0.05 and found 33 differential metabolites in elderly men and 30 differential metabolites in elderly women that could be potential biomarkers for OP. 2-Aminomuconic acid semialdehyde (AUC=0.72, 95% CI 0.582-0.857, P=0.004) is highly likely to be a biomarker for screening OP in older men. Tetradecanedioic acid (AUC=0.70, 95% CI 0.575-0.818, P=0.004) is highly likely to be a biomarker for screening OP in older women.
Conclusion: These findings can be applied to clinical work through further validation studies. This study also shows that metabolomic analysis has great potential for application in the early diagnosis and recurrence monitoring of OP in elderly individuals.

Keywords:  biomarkers; gas chromatography; liquid chromatography; mass spectrometry; osteoporosis; untargeted metabolomics

DOI:  https://doi.org/10.3389/fendo.2023.1332216
Regen Ther. 2024 Mar;25 250-263

Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human iPSC-derived neural models.

Sopak Supakul, Chisato Oyama, Yuki Hatakeyama, Sumihiro Maeda, Hideyuki Okano.

  Introduction: 17β-Estradiol (E2) is a sex hormone that has been previously demonstrated to have neurotherapeutic effects on animal models of Alzheimer's disease (AD). However, clinical trials on E2 replacement therapy for preventing AD onset yielded inconsistent results. Therefore, it is imperative to clarify the therapeutic effects of E2 on human cells. In this study, we utilized induced pluripotent stem cells (iPSCs) derived from multiple AD donors to explore the therapeutic effects of E2 on the in vitro model of human cells.Methods: We conducted a systematic review and meta-analysis using a random-effects model of the previously reported AD clinical trials to summarize the effects of E2 replacement therapy on AD prevention. Subsequently, we induced iPSCs from the donors of the healthy control (1210B2 line (female) and 201B7 line (female)), the familial AD (APP V717L line (female) and APP KM670/671NL line (female)), and the sporadic AD (UCSD-SAD3.7 line (APOE ε3/ε3) (male), UCSD-SAD7D line (APOE ε3/ε4) (male), and TMGH-1 line (APOE ε3/ε3) (female)), then differentiated to neurons. In addition to the mono-culture model of the neurons, we also examined the effects of E2 on the co-culture model of neurons and astrocytes.
Results: The meta-analysis of the clinical trials concluded that E2 replacement therapy reduced the risk of AD onset (OR, 0.69; 95 % confidence interval [CI], 0.53-0.91; I2 = 82 %). Neural models from the iPSCs of AD donors showed an increase in secreted amyloid-beta (Aβ) levels in the mono-culture model and an astrogliosis-like phenotype in the co-culture model. E2 treatment to the neuronal models derived from the iPSCs enhanced neuronal activity and increased neurite complexity. Furthermore, E2 treatment of the co-culture model ameliorated the astrogliosis-like phenotype. However, in contrast to the previous reports using mouse models, E2 treatment did not change AD pathogenesis, including Aβ secretion and phosphorylated tau (pTau) accumulation.
Conclusion: E2 treatment of the human cellular model did not impact Aβ secretion and pTau accumulation, but promoted neuronal plasticity and alleviated the astrogliosis-like phenotype. The limited effects of E2 may give a clue for the mixed results of E2 clinical trials.

Keywords:  17β-estradiol; Alzheimer's disease; Astrocytes; Induced pluripotent stem cells (iPSCs); Neurons

DOI:  https://doi.org/10.1016/j.reth.2023.12.018
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
Anticancer Agents Med Chem. 2024 Jan 04.

Synthesis of a Novel Gold(I) Complex and Evaluation of Its Anticancer Properties in Breast Cancer Cells.

Haseeb A Khan, Anvarhusein A Isab, Abdullah S Alhomida, Mansour K Gatasheh, Ali Al-Hoshani, Bashayr A Aldhafeeri, N Rajendra Prasad.

  BACKGROUND: Platinum complexes are commonly used for cancer chemotherapy; however, they are not only highly-priced but also have various side effects. It is, therefore, important to design affordable anticancer drugs with minimal side effects.METHODS: We synthesized a new gold(I) complex, PF6{(BDPEA)(TPPMS) digold(I)} (abbreviated as PBTDG) and tested its cytotoxicity of MCF-7 breast cancer cells. We also evaluated the effects of PBTDG on mitochondrial membrane potential, generation of reactive oxygen species (ROS) and apoptosis in breast cancer cells.
RESULTS: The IC50 values for PBTDG and sorafenib were found to be 1.48 μM and 4.45 μM, respectively. Exposure to PBTDG caused significant and concentration-dependent depletion of ATP and disruption of mitochondrial membrane potential. PBTDG induced 2.6, 3.6, and 5.7-fold apoptosis for 1 μM, 3 μM, and 10 μM concentrations, respectively. The induction of apoptosis by the same concentrations of sorafenib was 1.2, 1.3, and 1.6-fold, respectively. The low concentration of PBTDG (1 μM) induced the generation of ROS by 99.83%, which was significantly higher than the ROS generation caused by the same concentration of sorafenib (73.76%). The ROS induction caused by higher concentrations (5 μM) of PBTDG and sorafenib were 104.95% and 122.11%, respectively.
CONCLUSION: The lower concentration of PBTDG produced similar cytotoxicity and apoptotic effects that were caused by a comparatively higher concentration of known anticancer drug (sorafenib). The anticancer effects of PBTDG are attributed to its tendency to disrupt mitochondrial membrane potential, induction of apoptosis and generation of ROS. Further studies are warranted to test the anticancer effects of PBTDG in animal models of cancer.

Keywords:  Gold(I) complex; anticancer; apoptosis; cytotoxicity; mitochondrial membrane potential; reactive oxygen species.

DOI:  https://doi.org/10.2174/0118715206281182231127113608
Front Mol Neurosci. 2023 ;16 1333745

Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3.

Patrizia Ratano, Germana Cocozza, Cecilia Pinchera, Ludovica Maria Busdraghi, Iva Cantando, Katiuscia Martinello, Mariarosaria Scioli, Maria Rosito, Paola Bezzi, Sergio Fucile, Heike Wulff, Cristina Limatola, Giuseppina D'Alessandro.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse or control its progression. In the present study, taking advantage of a human superoxide dismutase-1 mutant (hSOD1-G93A) mouse that recapitulates key pathological features of human ALS, we investigated the possible role of voltage-gated potassium channel Kv1.3 in disease progression. We found that chronic administration of the brain-penetrant Kv1.3 inhibitor, PAP-1 (40 mg/Kg), in early symptomatic mice (i) improves motor deficits and prolongs survival of diseased mice (ii) reduces astrocyte reactivity, microglial Kv1.3 expression, and serum pro-inflammatory soluble factors (iii) improves structural mitochondrial deficits in motor neuron mitochondria (iv) restores mitochondrial respiratory dysfunction. Taken together, these findings underscore the potential significance of Kv1.3 activity as a contributing factor to the metabolic disturbances observed in ALS. Consequently, targeting Kv1.3 presents a promising avenue for modulating disease progression, shedding new light on potential therapeutic strategies for ALS.

Keywords:  ALS; Kv1.3 channels; inflammation; mitochondria; mutant SOD1

DOI:  https://doi.org/10.3389/fnmol.2023.1333745
Proc Nutr Soc. 2024 Feb 02. 1-21

Estrogens, Adipose Tissues, and Environmental Exposures Influence Obesity and Diabetes Across the Lifecycle.

Olgert Bardhi, Pallavi Dubey, Biff F Palmer, Deborah J Clegg.

Endogenous estrogens regulate essential functions to include menstrual cycles, energy balance, adipose tissue distribution, pancreatic β-cell function, insulin sensitivity, and lipid homeostasis. Estrogens are a family of hormones which include estradiol (E2), estrone (E1), and estriol (E3). Estrogens function by binding and activating estrogen receptors (ERs). Phytoestrogens are plant-derived compounds which exhibit estrogenic-like activity and can bind to ERs. Phytoestrogens exert potential estrogenic-like benefits; however, their effects are context-dependent and require cautious consideration regarding generalized health benefits. Xenoestrogens are synthetic compounds which have been determined to disrupt endocrine function through binding to ERs. Xenoestrogens enter the body through various routes and given their chemical structure they can accumulate, posing long-term health risks. Xenoestrogens interfere with endogenous estrogens and their functions contributing to conditions like cancer, infertility, and metabolic disorders. Understanding the interplay between endogenous and exogenous estrogens is critical in order to determine their potential health consequences and requires further investigation. This manuscript provides a summary of the role endogenous estrogens have in regulating metabolic functions. Additionally, we discuss the impact phytoestrogens and synthetic xenoestrogens have on biological systems across various life stages. We highlight their mechanisms of action, potential benefits, risks, and discuss the need for further research to bridge gaps in understanding and mitigate exposure-related health risks.

DOI: https://doi.org/10.1017/S0029665124000119
Endocrinology. 2024 Feb 01. pii: bqae012. [Epub ahead of print]

Lifespan effects of muscle-specific androgen receptor overexpression on body composition of male and female rats.

Sabrina Tzivia Barsky, Douglas Ashley Monks.

  Androgenic actions of gonadal testosterone are thought to be a major mechanism promoting sex differences in body composition across the lifespan. However, this inference is based on studies of androgen receptor (AR) function in late adolescent or emerging adult rodents. Here we assess body composition and AR expression in skeletal muscle of rats at defined ages, comparing wild-type (WT) to transgenic HSAAR rats which overexpress AR in skeletal muscle. Male and female HSAAR and WT Sprague Dawley rats (N = 288) underwent DXA scanning and tissue collection at post-natal day (PND) 1, 10, 21, 42, 70, 183, 243, and 365. Expected sex differences in body composition and muscle mass largely onset with puberty (PND-21), with no associated changes to skeletal muscle AR protein. In adulthood, HSAAR increased tibialis anterior (TA) and extensor digitorum longus mass in males, and reduced the expected gain in gonadal fat mass in both sexes. In WT rats, AR protein was reduced in soleus, but not TA, throughout life. Nonetheless, soleus AR protein expression was greater in males than females at all ages of sexual development, yet only at PND-70 in TA. Overall, despite muscle AR overexpression effects, results are inconsistent with major sex differences in body composition during sexual development being driven by changes in muscle AR, rather suggesting that changes in ligand promote sexual differentiation of body composition during pubertal timing. Nonetheless, increased skeletal muscle AR in adulthood can be sufficient to increase muscle mass in males, and reduce adipose in both sexes.

Keywords:  aging; body composition; lifespan; muscle androgen receptor; sex differences

DOI:  https://doi.org/10.1210/endocr/bqae012
Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00018-8. [Epub ahead of print]1870(3): 167033

The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.

Valeria Balmaceda, Timea Komlódi, Marten Szibor, Erich Gnaiger, Anthony L Moore, Erika Fernandez-Vizarra, Carlo Viscomi.

  Mitochondrial disorders are hallmarked by the dysfunction of oxidative phosphorylation (OXPHOS) yet are highly heterogeneous at the clinical and genetic levels. Striking tissue-specific pathological manifestations are a poorly understood feature of these conditions, even if the disease-causing genes are ubiquitously expressed. To investigate the functional basis of this phenomenon, we analyzed several OXPHOS-related bioenergetic parameters, including oxygen consumption rates, electron transfer system (ETS)-related coenzyme Q (mtCoQ) redox state and production of reactive oxygen species (ROS) in mouse brain and liver mitochondria fueled by different substrates. In addition, we determined how these functional parameters are affected by ETS impairment in a tissue-specific manner using pathologically relevant mouse models lacking either Ndufs4 or Ttc19, leading to Complex I (CI) or Complex III (CIII) deficiency, respectively. Detailed OXPHOS analysis revealed striking differences between brain and liver mitochondria in the capacity of the different metabolic substrates to fuel the ETS, reduce the ETS-related mtCoQ, and to induce ROS production. In addition, ETS deficiency due to either CI or CIII dysfunction had a much greater impact on the intrinsic bioenergetic parameters of brain compared with liver mitochondria. These findings are discussed in terms of the still rather mysterious tissue-specific manifestations of mitochondrial disease.

Keywords:  Coenzyme Q redox state; Complex I deficiency; Complex III deficiency; Isolated mitochondria; Oxygen consumption; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bbadis.2024.167033