bims-mifefi 2024-02-25 papers

bims-mifefi

Biomed News

on Mitochondria and female physiology

Issue of 2024‒02‒25
twelve papers selected by
Kayla Vandiver, East Carolina University

Control of muscle satellite cell function by specific exercise-induced cytokines and their applications in muscle maintenance.
Mitochondrial quality control alterations and placenta-related disorders.
GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.
In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.
Metabolomic Profiling of Blood Plasma in Females with Hyperplasia and Endometrial Cancer.
An integral role of mitochondrial function in the pathophysiology of preeclampsia.
Modulation of Estrogen Receptor Alpha (ERα) and Tumor Suppressor Gene BRCA1 in Breast Cancer Cells by Bazedoxifene Acetate (BZA).
Myoglobin deficiency impairs maximal oxygen uptake and exercise performance: a lesson from Mb-/- mice.
Celebrating a decade of exercise physiology and metabolism research in physiological reports.
Assessments of individual fiber glycogen and mitochondrial volume percentages reveal a graded reduction in muscle oxidative power during prolonged exhaustive exercise.
Sex differences in energy balance, body composition, and metabolic and endocrine markers during prolonged arduous military training.
Sex-Specific Mortality Benefits Related to Exercise.

J Cachexia Sarcopenia Muscle. 2024 Feb 20.

Control of muscle satellite cell function by specific exercise-induced cytokines and their applications in muscle maintenance.

Qian Guo, Qing Luo, Guanbin Song.

  Exercise is recognized to play an observable role in improving human health, especially in promoting muscle hypertrophy and intervening in muscle mass loss-related diseases, including sarcopenia. Recent rapid advances have demonstrated that exercise induces the release of abundant cytokines from several tissues (e.g., liver, muscle, and adipose tissue), and multiple cytokines improve the functions or expand the numbers of adult stem cells, providing candidate cytokines for alleviating a wide range of diseases. Muscle satellite cells (SCs) are a population of muscle stem cells that are mitotically quiescent but exit from the dormancy state to become activated in response to physical stimuli, after which SCs undergo asymmetric divisions to generate new SCs (stem cell pool maintenance) and commit to later differentiation into myocytes (skeletal muscle replenishment). SCs are essential for the postnatal growth, maintenance, and regeneration of skeletal muscle. Emerging evidence reveals that exercise regulates muscle function largely via the exercise-induced cytokines that govern SC potential, but this phenomenon is complicated and confusing. This review provides a comprehensive integrative overview of the identified exercise-induced cytokines and the roles of these cytokines in SC function, providing a more complete picture regarding the mechanism of SC homeostasis and rejuvenation therapies for skeletal muscle.

Keywords:  Cytokines; Exercise; Homeostasis; Muscle satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13440
Front Physiol. 2024 ;15 1344951

Mitochondrial quality control alterations and placenta-related disorders.

Yamei Wu, Meng Li, Hao Ying, Ying Gu, Yunlong Zhu, Yanfang Gu, Lu Huang.

  Mitochondria are ubiquitous in eukaryotic cells. Normal maintenance of function is the premise and basis for various physiological activities. Mitochondrial dysfunction is commonly observed in a wide range of pathological conditions, such as neurodegenerative, metabolic, cardiovascular, and various diseases related to foetal growth and development. The placenta is a highly energy-dependent organ that acts as an intermediary between the mother and foetus and functions to maintain foetal growth and development. Recent studies have demonstrated that mitochondrial dysfunction is associated with placental disorders. Defects in mitochondrial quality control mechanisms may lead to preeclampsia and foetal growth restriction. In this review, we address the quality control mechanisms of mitochondria and the relevant pathologies of mitochondrial dysfunction in placenta-related diseases, such as preeclampsia and foetal growth restriction. This review also investigates the relation between mitochondrial dysfunction and placental disorders.

Keywords:  foetal growth restriction; mitochondria; mitochondrial dysfunction; placenta; preeclampsia

DOI:  https://doi.org/10.3389/fphys.2024.1344951
Cells. 2024 Feb 08. pii: 316. [Epub ahead of print]13(4):

GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.

Catalina M Polanco, Viviana A Cavieres, Abigail J Galarza, Claudia Jara, Angie K Torres, Jorge Cancino, Manuel Varas-Godoy, Patricia V Burgos, Cheril Tapia-Rojas, Gonzalo A Mardones.

  In this study, we investigated the inter-organelle communication between the Golgi apparatus (GA) and mitochondria. Previous observations suggest that GA-derived vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) play a role in mitochondrial fission, colocalizing with DRP1, a key protein in this process. However, the functions of these vesicles and potentially associated proteins remain unknown. GOLPH3, a PI(4)P-interacting GA protein, is elevated in various types of solid tumors, including breast cancer, yet its precise role is unclear. Interestingly, GOLPH3 levels influence mitochondrial mass by affecting cardiolipin synthesis, an exclusive mitochondrial lipid. However, the mechanism by which GOLPH3 influences mitochondria is not fully understood. Our live-cell imaging analysis showed GFP-GOLPH3 associating with PI(4)P vesicles colocalizing with YFP-DRP1 at mitochondrial fission sites. We tested the functional significance of these observations with GOLPH3 knockout in MDA-MB-231 cells of breast cancer, resulting in a fragmented mitochondrial network and reduced bioenergetic function, including decreased mitochondrial ATP production, mitochondrial membrane potential, and oxygen consumption. Our findings suggest a potential negative regulatory role for GOLPH3 in mitochondrial fission, impacting mitochondrial function and providing insights into GA-mitochondria communication.

Keywords:  DRP1; GOLPH3; Golgi apparatus; Golgi–mitochondria communication; PI(4)P; mitochondrial bioenergetics; mitochondrial fission and fusion; mitochondrial fragmentation

DOI:  https://doi.org/10.3390/cells13040316
J Physiol. 2024 Feb 21.

In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.

Zhongchao Wang, Emily J Camm, Anna Maria Nuzzo, Ana-Mishel Spiroski, Katie L Skeffington, Thomas J Ashmore, Alessandro Rolfo, Tullia Todros, Angela Logan, Jin Ma, Michael P Murphy, Youguo Niu, Dino A Giussani.

  Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy ± daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.

Keywords:  chronic hypoxia; fetal growth restriction; pre-eclampsia; uterine PI

DOI:  https://doi.org/10.1113/JP286178
Metabolites. 2024 Feb 06. pii: 109. [Epub ahead of print]14(2):

Metabolomic Profiling of Blood Plasma in Females with Hyperplasia and Endometrial Cancer.

Hicham Benabdelkamel, Malak A Jaber, Khalid Akkour, Reem H AlMalki, Assim A Alfadda, Afshan Masood, Salini Scaria Joy, Hani Alhalal, Moudi A Alwehaibi, Maria Arafah, Eman Alshehri, Anas M Abdel Rahman.

  Uterine cancer is the most prevalent gynecologic malignancy in women worldwide. Endometrial cancer (EC) has an 81% five-year survival rate, depending on disease stage and time of diagnosis. While endometrial cancer is largely treatable when detected early, no established screening techniques are available in clinical practice. As a result, one of the most significant issues in the medical field is the development of novel ways for early cancer identification, which could boost treatment success rates. Liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based metabolomics was employed to explore the metabolomic markers and pathways unique to this cancer type and link them to the benign endometrial hyperplasia that may progress to cancer in 5% to 25% of patients. The study involved 59 postmenopausal participants, 20 with EC type 1, 20 with benign hyperplasia, and 19 healthy participants. Metabolite distribution changes were analyzed, and 338 of these features were dysregulated and significant. The first two main components, PC1 and PC2, were responsible for 11.5% and 12.2% of the total metabolites, respectively. Compared with the control group (CO), EC samples had 203 differentially expressed metabolites (180 upregulated and 23 downregulated); in hyperplasia (HP), 157 metabolites were dysregulated (127 upregulated and 30 downregulated) compared to the CO group while 21 metabolites exhibited differential regulation (16 upregulated and 5 downregulated) in EC plasma samples compared to the HP group. Hyperplasia samples exhibited similar metabolic changes to those reported in cancer, except for alterations in triglyceride levels, 7a,12 b-dihydroxy-5b-Cholan-24-oic acid, and Hept-2-enedioyl carnitine levels. The metabolites N-heptanoyl glycine and -(Methylthio)-2,3-isopentyl phosphate and formimino glutamic acid can be specific markers for hyperplasia conditions and dimethyl phosphatidyl ethanolamine and 8-isoprostaglandin E2 can be specific markers for EC conditions. Metabolic activities rely on mitochondrial oxidative phosphorylation for energy generation. The changes in metabolites identified in our study indicate that endometrial cancer cells adopt alternative strategies to increase energy production to meet the energy demand, thereby supporting proliferation.

Keywords:  LC-HRMS; endometrial cancer; energy metabolism; hyperplasia (HP); metabolomics

DOI:  https://doi.org/10.3390/metabo14020109
Mol Biol Rep. 2024 Feb 23. 51(1): 330

An integral role of mitochondrial function in the pathophysiology of preeclampsia.

Hiroshi Kobayashi, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi, Shogo Imanaka.

  Preeclampsia (PE) is associated with high maternal and perinatal morbidity and mortality. The development of effective treatment strategies remains a major challenge due to the limited understanding of the pathogenesis. In this review, we summarize the current understanding of PE research, focusing on the molecular basis of mitochondrial function in normal and PE placentas, and discuss perspectives on future research directions. Mitochondria integrate numerous physiological processes such as energy production, cellular redox homeostasis, mitochondrial dynamics, and mitophagy, a selective autophagic clearance of damaged or dysfunctional mitochondria. Normal placental mitochondria have evolved innovative survival strategies to cope with uncertain environments (e.g., hypoxia and nutrient starvation). Cytotrophoblasts, extravillous trophoblast cells, and syncytiotrophoblasts all have distinct mitochondrial morphology and function. Recent advances in molecular studies on the spatial and temporal changes in normal mitochondrial function are providing valuable insight into PE pathogenesis. In PE placentas, hypoxia-mediated mitochondrial fission may induce activation of mitophagy machinery, leading to increased mitochondrial fragmentation and placental tissue damage over time. Repair mechanisms in mitochondrial function restore placental function, but disruption of compensatory mechanisms can induce apoptotic death of trophoblast cells. Additionally, molecular markers associated with repair or compensatory mechanisms that may influence the development and progression of PE are beginning to be identified. However, contradictory results have been obtained regarding some of the molecules that control mitochondrial biogenesis, dynamics, and mitophagy in PE placentas. In conclusion, understanding how the mitochondrial morphology and function influence cell fate decisions of trophoblast cells is an important issue in normal as well as pathological placentation biology. Research focusing on mitochondrial function will become increasingly important for elucidating the pathogenesis and effective treatment strategies of PE.

Keywords:  Biogenesis; Dynamics; Mitochondria; Mitophagy; Preeclampsia

DOI:  https://doi.org/10.1007/s11033-024-09285-z
Cancers (Basel). 2024 Feb 07. pii: 699. [Epub ahead of print]16(4):

Modulation of Estrogen Receptor Alpha (ERα) and Tumor Suppressor Gene BRCA1 in Breast Cancer Cells by Bazedoxifene Acetate (BZA).

Monica Szmyd, Aisha Zanib, Victoria Behlow, Erin Hallman, Samantha Pfiffner, Raquel Yaldo, Nina Prudhomme, Katelyn Farrar, Sumi Dinda.

  Selective estrogen receptor modulators (SERMs) are steroid analogs with dual functionality, acting as partial estrogen receptor agonists to preserve postmenopausal bone density and as estrogen receptor antagonists in breast tissue. Bazedoxifene acetate (BZA) is an FDA-approved, third-generation SERM used in the treatment of osteoporosis in women. It demonstrates potential as a therapeutic option for breast cancer patients undergoing endocrine therapy. Our study aimed to assess BZA's effects on Estrogen Receptor Alpha (ERα) and tumor suppressor gene BRCA1 in T-47D and MCF-7 breast cancer cells, using Western blots, cellular viability, apoptosis assays, and RT-qPCR. Cells were cultured in 5% charcoal-stripped fetal bovine serum for six days to deplete endogenous steroids. Following a 24 h exposure to 2 µM BZA (optimal concentration determined from 1 nM-2 µM studies), Western blot analyses revealed reduced ERα and BRCA1 protein levels in both cell lines. ERα decreased by 48-63% and BRCA1 by 61-64%, indicating sensitivity to antiestrogens. Cytolocalization of ERα and BRCA1 remained unchanged after BZA and 17-β-estradiol (E2) treatment. ESR1 mRNA expression correlated with Western blot findings. Image cytometric analysis using the stain, propidium iodide, detected decreased cellular proliferation in T-47D and MCF-7 cells following a 6-day treatment ranging from 1 nM to 2 µM BZA. BZA treatment alone led to a tenfold reduction in cellular proliferation compared to estrogen-treated cells, suggesting antiproliferative effects. Understanding BZA's modulation of BRCA1 and ERα, along with their mechanistic interactions, is vital for comprehending its impact on breast cancer tumor suppressors and hormone receptors.

Keywords:  BRCA1; ERα; bazedoxifene acetate; breast cancer; estrogen receptor; selective estrogen receptor modulators; tumor suppressor gene

DOI:  https://doi.org/10.3390/cancers16040699
J Physiol. 2024 Feb 20.

Myoglobin deficiency impairs maximal oxygen uptake and exercise performance: a lesson from Mb-/- mice.

Jerzy A Zoladz, Marcin Grandys, Marta Smeda, Agnieszka Kij, Anna Kurpinska, Grzegorz Kwiatkowski, Janusz Karasinski, Ulrike Hendgen-Cotta, Stefan Chlopicki, Joanna Majerczak.

  Myoglobin (Mb) plays an important role at rest and during exercise as a reservoir of oxygen and has been suggested to regulate NO• bioavailability under hypoxic/acidic conditions. However, its ultimate role during exercise is still a subject of debate. We aimed to study the effect of Mb deficiency on maximal oxygen uptake ( V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and exercise performance in myoglobin knockout mice (Mb-/- ) when compared to control mice (Mb+/+ ). Furthermore, we also studied NO• bioavailability, assessed as nitrite (NO2 - ) and nitrate (NO3 - ) in the heart, locomotory muscle and in plasma, at rest and during exercise at exhaustion both in Mb-/- and in Mb+/+ mice. The mice performed maximal running incremental exercise on a treadmill with whole-body gas exchange measurements. The Mb-/- mice had lower body mass, heart and hind limb muscle mass (P < 0.001). Mb-/- mice had significantly reduced maximal running performance (P < 0.001). V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$ expressed in ml min-1 in Mb-/ - mice was 37% lower than in Mb+/+ mice (P < 0.001) and 13% lower when expressed in ml min-1 kg body mass-1 (P = 0.001). Additionally, Mb-/- mice had significantly lower plasma, heart and locomotory muscle NO2 - levels at rest. During exercise NO2 - increased significantly in the heart and locomotory muscles of Mb-/- and Mb+/+ mice, whereas no significant changes in NO2 - were found in plasma. Our study showed that, contrary to recent suggestions, Mb deficiency significantly impairs V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance in mice. KEY POINTS: Myoglobin knockout mice (Mb-/- ) possess lower maximal oxygen uptake ( V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and poorer maximal running performance than control mice (Mb+/+ ). Respiratory exchange ratio values at high running velocities in Mb-/- mice are higher than in control mice suggesting a shift in substrate utilization towards glucose metabolism in Mb-/- mice at the same running velocities. Lack of myoglobin lowers basal systemic and muscle NO• bioavailability, but does not affect exercise-induced NO2 - changes in plasma, heart and locomotory muscles. The present study demonstrates that myoglobin is of vital importance for V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance as well as explains why previous studies have failed to prove such a role of myoglobin when using the Mb-/- mouse model.

Keywords:  V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$; nitrate; nitric oxide; nitrite; respiratory exchange ratio; running performance

DOI:  https://doi.org/10.1113/JP285067
Physiol Rep. 2024 Feb;12(4): e15960

Celebrating a decade of exercise physiology and metabolism research in physiological reports.

David C Wright, Arthur J Cheng, Rebecca E K MacPherson.

  During its first decade of life, Physiological Reports has become a home for well-conceived and rigorously performed exercise physiology and metabolism studies. The breadth of research within this area is impressive, covering exercise-induced increases in skeletal muscle gene expression to the effects of exercise on the gut microbiome. The purpose of the current review is to highlight some of the impactful exercise physiology and metabolism papers published in the journal and to look ahead to what areas exercise physiology publications might address in the next 10 years.

Keywords:  adipose tissue; exercise; metabolism; microbiome; muscle

DOI:  https://doi.org/10.14814/phy2.15960
Scand J Med Sci Sports. 2024 Feb;34(2): e14571

Assessments of individual fiber glycogen and mitochondrial volume percentages reveal a graded reduction in muscle oxidative power during prolonged exhaustive exercise.

Joachim Nielsen, Rasmus Jensen, Niels Ørtenblad.

  During submaximal exercise, there is a heterogeneous recruitment of skeletal muscle fibers, with an ensuing heterogeneous depletion of muscle glycogen both within and between fiber types. Here, we show that the mean (95% CI) mitochondrial volume as a percentage of fiber volume of non-glycogen-depleted fibers was 2 (-10:6), 5 (-21:11), and 12 (-21:-2)% lower than all the sampled fibers after continuing exercise for 1, 2 h, and until task failure, respectively. Therefore, a glycogen-dependent fatigue of individual fibers during submaximal exercise may reduce the muscular oxidative power. These findings suggest a relationship between glycogen and mitochondrial content in individual muscle fibers, which is important for understanding fatigue during prolonged exercise.

Keywords:  exercise; fatigue; glycogen; mitochondria; muscle fiber; transmission electron microscopy

DOI:  https://doi.org/10.1111/sms.14571
J Appl Physiol (1985). 2024 Feb 22.

Sex differences in energy balance, body composition, and metabolic and endocrine markers during prolonged arduous military training.

Thomas J O'Leary, Robert M Gifford, Rebecca L Knight, Jennifer Wright, Sally Handford, Michelle C Venables, Rebecca M Reynolds, David Woods, Sophie L Wardle, Julie P Greeves.

  This study investigated sex differences in energy balance, body composition, and metabolic and endocrine markers during prolonged military training. Twenty-three trainees (14 women) completed 44-weeks military training (three terms of 14 weeks with 2 weeks adventurous training). Dietary intake and total energy expenditure were measured over 10 days during each term by weighed food and doubly labelled water. Body composition was measured by DXA at baseline and the end of each term. Circulating metabolic and endocrine markers were measure at baseline and the end of terms 2 and 3. Absolute energy intake and total energy expenditure were higher, and energy balance was lower, for men than women (p ≤ 0.008). Absolute energy intake and balance were lower, and total energy expenditure was higher, during term 2 than terms 1 and 3 (p < 0.001). Lean mass did not change with training (p = 0.081). Fat mass and body fat increased from term 1 to terms 2 and 3 (p ≤ 0.045). Leptin increased from baseline to terms 2 and 3 in women (p ≤ 0.002) but not men (p ≥ 0.251). Testosterone and free androgen index increased from baseline to term 3 (p ≤ 0.018). Free T4 decreased and TSH increased from baseline to term 2 and term 3 (p ≤ 0.031). Cortisol decreased from baseline to term 3 (p = 0.030). IGF-I and total T3 did not change with training (p ≥ 0.148). Men experienced greater energy deficits than women during military training due to higher total energy expenditure.

Keywords:  Body composition; Musculoskeletal injury; Nutrition; Performance

DOI:  https://doi.org/10.1152/japplphysiol.00864.2023
J Am Coll Cardiol. 2024 Feb 27. pii: S0735-1097(24)00048-2. [Epub ahead of print]83(8): 794-796

Sex-Specific Mortality Benefits Related to Exercise.

Wael A Jaber, Erika Hutt.



Keywords:  mortality; physical activity; sex differences

DOI:  https://doi.org/10.1016/j.jacc.2024.01.003