bims-midhyp 2023-09-10 papers

bims-midhyp

Biomed News

on Mitochondrial dysfunction and hypoxia

Issue of 2023‒09‒10
twenty-two papers selected by
Alia Abukiwan, University of Heidelberg

Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.
The mechanism and targeted intervention of the HIF-1 pathway in improving atherosclerotic heart's sensitivity to ischemic postconditioning.
Mitochondrial dynamics in health and disease: mechanisms and potential targets.
Oxygen Variations-Insights into Hypoxia, Hyperoxia and Hyperbaric Hyperoxia-Is the Dose the Clue?
Hypoxia and hypoxia-inducible factors in Kaposi sarcoma-associated herpesvirus infection and disease pathogenesis.
Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress.
Sodium Butyrate as Key Regulator of Mitochondrial Function and Barrier Integrity of Human Glomerular Endothelial Cells.
Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.
Expression of hypoxia-inducible genes is suppressed in altered gravity due to impaired nuclear HIF1α accumulation.
Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes.
Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases.
Hypoxia-inducible Factor-1α and mTOR as a Potential Therapeutic Target in Endometriosis: An Immunohistochemical Study.
Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology.
Cardiac Metabolism, Reprogramming, and Diseases.
Mechanisms and pathology of protein misfolding and aggregation.
eIF3d controls the persistent integrated stress response.
The role of mitochondrial dynamics in the pathophysiology of endometriosis.
Mitochondrial Factors in the Cell Nucleus.
Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.
Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.
Hypoxia improves self-renew and migration of urine stem cells by upregulating autophagy and mitochondrial function through ERK signal pathway.
Circulating Exosomes from Alzheimer's Disease Suppress Vascular Endothelial-Cadherin Expression and Induce Barrier Dysfunction in Recipient Brain Microvascular Endothelial Cell.

Dev Cell. 2023 Sep 01. pii: S1534-5807(23)00411-2. [Epub ahead of print]

Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.

Alexandra MacColl Garfinkel, Nelli Mnatsakanyan, Jeet H Patel, Andrea E Wills, Amy Shteyman, Peter J S Smith, Kambiz N Alavian, Elizabeth Ann Jonas, Mustafa K Khokha.

  An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the "free" c-subunit ring of the F1Fo ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when β-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.

Keywords:  F(1)F(o) ATP synthase; Hif-1α; LRPPRC; Spemann-Mangold Organizer; Wnt/β-catenin signaling; Xenopus; free c-subunit; hypoxia; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.devcel.2023.08.015
Free Radic Biol Med. 2023 Sep 01. pii: S0891-5849(23)00610-X. [Epub ahead of print]

The mechanism and targeted intervention of the HIF-1 pathway in improving atherosclerotic heart's sensitivity to ischemic postconditioning.

Xue Yang, Jiang Wang, Xiaowen Dai, Ning Ma, Hu Cheng, Hai Guo, Siyu Chen, Yidan Huang, Jianjiang Wu.

  BACKGROUND: IPoC possesses a preventive effect against IR injury in healthy myocardium, but IPoC's protective effect on atherosclerotic myocardium is controversial. The current investigation aims to determine whether IPoC remains protective in atherosclerotic myocardium subjected to ischemia-reperfusion (IR) injury; to explore the specific mechanisms by which IPoC exerts cardioprotection; to explore whether HIF-1 upregulation combined with IPoC could further the provide cardioprotection; and to gaze at the specific mechanism whereby combined treatment expert the cardioprotection.METHODS: ApoE-/- mice fed with a high-fat diet (HFD) were used to develop a model of atherosclerosis. The myocardial IR model was induced by occlusion of the left anterior descending (LAD) artery for 45 min, followed by reperfusion for 120 min. The protection of IPoC in both healthy and atherosclerotic myocardium was evaluated by measuring oxidative stress, apoptosis, infarct size, pathology, mitochondrial dysfunction and morphology of myocardium. The specific mechanism by which IPoC exerts cardioprotection in healthy and atherosclerotic myocardium was observed by measuring the expression of proteins involved in HIF-1, APMK and RISK pathways. The effect of HIF-1α overexpression on the cardioprotection by IPoC was observed by intravenous AAV9 -HIF-1α injection.
RESULTS: In healthy ischemic myocardium, IPoC exerted myocardial protective effects (antioxidant, anti-apoptosis, and improved mitochondrial function) through the activation of HIF-1, AMPK and RISK pathways. In atherosclerotic ischemic myocardium, IPoC exerted cardioprotection only through the activation of HIF-1 pathway; however, HIF-1overexpression combined IPoC restored the activation of AMPK and RISK pathways, thereby further alleviate the myocardial IR injury.
CONCLUSIONS: In the atherosclerotic state, the HIF-1 pathway is the intrinsic mechanism by which IPoC exerts cardioprotective effects. The combination of HIF-1 upregulation and IPoC has a significant effect in reducing myocardial injury, which is worth being promoted and advocated. In addition, HIF-1-AMPK and HIF-1-RISK may be two endogenous cardioprotective signalling pathways with great value, which deserve to be thoroughly investigated in the future.

Keywords:  Adenosine monophosphate-activated protein kinase; Atherosclerosis; Hypoxia-inducible factor 1; Ischemic postconditioning; Myocardial ischemia-reperfusion injury; Reperfusion injury salvage kinase

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.030
Signal Transduct Target Ther. 2023 Sep 06. 8(1): 333

Mitochondrial dynamics in health and disease: mechanisms and potential targets.

Wen Chen, Huakan Zhao, Yongsheng Li.

Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.

DOI: https://doi.org/10.1038/s41392-023-01547-9
Int J Mol Sci. 2023 Aug 30. pii: 13472. [Epub ahead of print]24(17):

Oxygen Variations-Insights into Hypoxia, Hyperoxia and Hyperbaric Hyperoxia-Is the Dose the Clue?

Costantino Balestra, Simona Mrakic-Sposta, Fabio Virgili.

Molecular oxygen (O2) is one of the four most important elements on Earth (alongside carbon, nitrogen and hydrogen); aerobic organisms depend on it to release energy from carbon-based molecules [...].

DOI: https://doi.org/10.3390/ijms241713472
J Med Virol. 2023 09;95(9): e29071

Hypoxia and hypoxia-inducible factors in Kaposi sarcoma-associated herpesvirus infection and disease pathogenesis.

David A Davis, Prabha Shrestha, Robert Yarchoan.

  Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma and several other tumors and hyperproliferative diseases seen predominantly in human immunodeficiency virus-infected and other immunocompromised persons. There is an increasing body of evidence showing that hypoxia and hypoxia-inducible factors (HIFs) play important roles in the biology of KSHV and in the pathogenesis of KSHV-induced diseases. Hypoxia and HIFs can induce lytic activation of KSHV and KSHV can in turn lead to a hypoxic-like state in infected cells. In this review, we describe the complex interactions between KSHV biology, the cellular responses to hypoxia, and the pathogenesis of KSHV-induced diseases. We also describe how interference with HIFs can lead to decreased tumor growth and/or death of infected cells and KSHV-induced tumors. Finally, we show how these observations may lead to novel strategies for the treatment of KSHV-induced diseases.

Keywords:  HIF-1; HIF-2; Kaposi sarcoma; gammaherpesvirus; hypoxia; hypoxia response element; viral malignancy

DOI:  https://doi.org/10.1002/jmv.29071
Neuroprotection. 2023 Sep;1(1): 9-19

Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress.

Hannelore Ehrenreich, Max Gassmann, Luise Poustka, Martin Burtscher, Peter Hammermann, Anna-Leena Sirén, Klaus-Armin Nave, Kamilla Miskowiak.

  Hypoxia is increasingly recognized as an important physiological driving force. A specific transcriptional program, induced by a decrease in oxygen (O2) availability, for example, inspiratory hypoxia at high altitude, allows cells to adapt to lower O2 and limited energy metabolism. This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors. Remarkably, this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise, leading to a relative decrease in O2 supply, compared to the acutely augmented O2 requirement. We have coined the term "functional hypoxia" for this important demand-responsive, relative reduction in O2 availability. Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial "brain hardware upgrade," underlying advanced performance. Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes, which can be imitated by recombinant human erythropoietin treatment. This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function. It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease. Finally, it sketches a planned multistep pilot study in healthy volunteers and first patients, about to start, aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.

Keywords:  HIF; PBMC; brain EPO circle; erythropoietin; functional hypoxia; human pilot study; hyperoxia; inspiratory oxygen manipulations; motor-cognitive performance; translation

DOI:  https://doi.org/10.1002/nep3.15
Int J Mol Sci. 2023 Aug 23. pii: 13090. [Epub ahead of print]24(17):

Sodium Butyrate as Key Regulator of Mitochondrial Function and Barrier Integrity of Human Glomerular Endothelial Cells.

Maria Novella Nicese, Roel Bijkerk, Anton Jan Van Zonneveld, Bernard M Van den Berg, Joris I Rotmans.

  The gut microbiota has emerged as an important modulator of cardiovascular and renal homeostasis. The composition of gut microbiota in patients suffering from chronic kidney disease (CKD) is altered, where a lower number of bacteria producing short chain fatty acids (SCFAs) is observed. It is known that SCFAs, such as butyrate and acetate, have protective effects against cardiovascular diseases and CKD but their mechanisms of action remain largely unexplored. In the present study, we investigated the effect of butyrate and acetate on glomerular endothelial cells. Human glomerular microvascular endothelial cells (hgMVECs) were cultured and exposed to butyrate and acetate and their effects on cellular proliferation, mitochondrial mass and metabolism, as well as monolayer integrity were studied. While acetate did not show any effects on hgMVECs, our results revealed that butyrate reduces the proliferation of hgMVECs, strengthens the endothelial barrier through increased expression of VE-cadherin and Claudin-5 and promotes mitochondrial biogenesis. Moreover, butyrate reduces the increase in oxygen consumption induced by lipopolysaccharides (LPS), revealing a protective effect of butyrate against the detrimental effects of LPS. Taken together, our data show that butyrate is a key player in endothelial integrity and metabolic homeostasis.

Keywords:  LPS; butyrate; endothelial barrier; glomerular endothelial cells; mitochondria; proliferation; seahorse; short chain fatty acids

DOI:  https://doi.org/10.3390/ijms241713090
Cell Discov. 2023 Sep 07. 9(1): 92

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.

Terytty Yang Li, Qi Wang, Arwen W Gao, Xiaoxu Li, Yu Sun, Adrienne Mottis, Minho Shong, Johan Auwerx.

Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from ROS-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.

DOI: https://doi.org/10.1038/s41421-023-00589-1
Sci Rep. 2023 09 04. 13(1): 14514

Expression of hypoxia-inducible genes is suppressed in altered gravity due to impaired nuclear HIF1α accumulation.

Mostafa A Aboouf, Cora S Thiel, Sergey M Borisov, Svantje Tauber, Eva Bönzli, Nelli Schetle, Oliver Ullrich, Max Gassmann, Johannes Vogel.

Extravehicular activities, the backbone of manned space exploration programs, set astronauts into mild hypoxia. Unfortunately, microgravity aggravates threatening symptoms of hypoxia such as vision impairment and brain edema. Hypoxia-inducible factors (HIFs) sense cellular hypoxia and, subsequently, change the cells' expression profile instantaneously by rapidly translocating-most likely cytoskeleton-dependently-into the nucleus and subsequently forming transcription complexes with other proteins. We tested the hypothesis that this fundamental process could be altered by sudden changes in gravitational forces in parabolic flights using a newly developed pocket-size cell culture lab that deoxygenizes cells within 15 min. Sudden gravity changes (SGCs 1g-1.8g-0g-1.8g-1g) during hypoxic exposure suppressed expression of the HIF1α-dependent genes investigated as compared with hypoxia at constant 1g. Normoxic cells subjected to SGCs showed reduced nuclear but not cytoplasmatic HIF1α signal and appeared to have disturbed cytoskeleton architecture. Inhibition of the actin-dependent intracellular transport using a combination of myosin V and VI inhibitors during hypoxia mimicked the suppression of the HIF1α-dependent genes observed during hypoxic exposure during SGCs. Thus, SGCs seem to disrupt the cellular response to hypoxia by impairing the actin-dependent translocation of HIF1α into the nucleus.

DOI: https://doi.org/10.1038/s41598-023-41686-1
Int J Mol Sci. 2023 Aug 22. pii: 13033. [Epub ahead of print]24(17):

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes.

Hubert Grel, Damian Woznica, Katarzyna Ratajczak, Ewelina Kalwarczyk, Julia Anchimowicz, Weronika Switlik, Piotr Olejnik, Piotr Zielonka, Magdalena Stobiecka, Slawomir Jakiela.

  Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration and death of neurons, leading to a range of neurological symptoms. Despite the heterogeneity of these conditions, a common denominator is the implication of mitochondrial dysfunction in their pathogenesis. Mitochondria play a crucial role in creating biomolecules, providing energy through adenosine triphosphate (ATP) generated by oxidative phosphorylation (OXPHOS), and producing reactive oxygen species (ROS). When they're not functioning correctly, becoming fragmented and losing their membrane potential, they contribute to these diseases. In this review, we explore how mitochondria fuse and undergo fission, especially in the context of NDs. We discuss the genetic and protein mutations linked to these diseases and how they impact mitochondrial dynamics. We also look at the key regulatory proteins in fusion (MFN1, MFN2, and OPA1) and fission (DRP1 and FIS1), including their post-translational modifications. Furthermore, we highlight potential drugs that can influence mitochondrial dynamics. By unpacking these complex processes, we aim to direct research towards treatments that can improve life quality for people with these challenging conditions.

Keywords:  mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; neurodegenerative disease; potential drugs

DOI:  https://doi.org/10.3390/ijms241713033
Redox Biol. 2023 Aug 29. pii: S2213-2317(23)00266-5. [Epub ahead of print]66 102865

Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases.

Tong Sun, Haiyang Yu, Danni Li, He Zhang, Jianhua Fu.

  Oxygen therapy is common during the neonatal period to improve survival, but it can increase the risk of oxygen toxicity. Hyperoxia can damage multiple organs and systems in newborns, commonly causing lung conditions such as bronchopulmonary dysplasia and pulmonary hypertension, as well as damage to other organs, including the brain, gut, and eyes. These conditions are collectively referred to as newborn oxygen radical disease to indicate the multi-system damage caused by hyperoxia. Hyperoxia can also lead to changes in metabolic pathways and the production of abnormal metabolites through a process called metabolic reprogramming. Currently, some studies have analyzed the mechanism of metabolic reprogramming induced by hyperoxia. The focus has been on mitochondrial oxidative stress, mitochondrial dynamics, and multi-organ interactions, such as the lung-gut, lung-brain, and brain-gut axes. In this article, we provide an overview of the major metabolic pathway changes reported in hyperoxia-associated neonatal diseases and explore the potential mechanisms of metabolic reprogramming. Metabolic reprogramming induced by hyperoxia can cause multi-organ metabolic disorders in newborns, including abnormal glucose, lipid, and amino acid metabolism. Moreover, abnormal metabolites may predict the occurrence of disease, suggesting their potential as therapeutic targets. Although the mechanism of metabolic reprogramming caused by hyperoxia requires further elucidation, mitochondria and the gut-lung-brain axis may play a key role in metabolic reprogramming.

Keywords:  Bronchopulmonary dysplasia; Hyperoxia; Metabolic reprogramming; Mitochondria; Neonate

DOI:  https://doi.org/10.1016/j.redox.2023.102865
Appl Immunohistochem Mol Morphol. 2023 Aug 30.

Hypoxia-inducible Factor-1α and mTOR as a Potential Therapeutic Target in Endometriosis: An Immunohistochemical Study.

Dalia M Badary, Hisham A Abou-Taleb, Maha Ibrahim.

BACKGROUND AND STUDY AIM: We aim to study the immunohistochemical expression of both hypoxia-inducible factor-1α (HIF-1α) and mammalian target of rapamycin (mTOR) in endometriosis to provide new evidence for a targeted endometriosis therapy.PATIENTS AND METHODS: This study comprised 106 endometriotic cases diagnosed clinically and histopathologically. The immunohistochemical method was done to determine the expression of HIF-1α and mTOR.
RESULTS: Endometriotic glands showed significant cytoplasmic expression of both markers in patients with poor ovulation, severe endometriosis, and infertile for >2 years (P<0.001). Also, patients with intense and worst pain show significant immunohistochemical expression of both markers (P<0.001). There is a significant correlation between mTOR and HIF-1α expression in endometriotic tissue samples as P<0.001.
CONCLUSIONS: Our data suggest that both mTOR and its downstream target HIF-1α transcription factor are both disrupted in patients with endometriosis, which is consistent with aberrant activation of these pathways and their possible contribution to the pathogenesis of endometriosis. These results could offer a promising novel opportunity to be blocked therapeutically. As new management options need to be refined in particular in severe cases and infertile patients with endometriosis, therefore future studies are warranted to investigate treating endometriosis with mTOR inhibitors; the latter are already in clinical trials in phase III and IV, treating solid tumors as well as non-neoplastic disorders.

DOI: https://doi.org/10.1097/PAI.0000000000001148
Int J Mol Sci. 2023 Aug 23. pii: 13123. [Epub ahead of print]24(17):

Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology.

Kyle M Siemers, Abigail K Klein, Michelle L Baack.

  Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease, all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under the transcriptional regulation of both the nuclear and mitochondrial genome to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, as well as the dynamics that regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted, the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function, causing disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs, including the ovary (oocytes and granulosa cells), uterus, placenta, and circulation, causing reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in the transgenerational transmission of PCOS and metabolic disorders.

Keywords:  PCOS; biogenesis; metabolism; mitochondria; mitochondrial dynamics; mtDNA; ovary; oxidative stress; placenta; polycystic ovary syndrome; uterus

DOI:  https://doi.org/10.3390/ijms241713123
J Cardiovasc Transl Res. 2023 Sep 05.

Cardiac Metabolism, Reprogramming, and Diseases.

Haichang Wang, Min Shen, Xiaofei Shu, Baolin Guo, Tengfei Jia, Jiaxu Feng, Zuocheng Lu, Yanyan Chen, Jie Lin, Yue Liu, Jiye Zhang, Xuan Zhang, Dongdong Sun.

  Cardiovascular diseases (CVD) account for the largest bulk of deaths worldwide, posing a massive burden on societies and the global healthcare system. Besides, the incidence and prevalence of these diseases are on the rise, demanding imminent action to revert this trend. Cardiovascular pathogenesis harbors a variety of molecular and cellular mechanisms among which dysregulated metabolism is of significant importance and may even proceed other mechanisms. The healthy heart metabolism primarily relies on fatty acids for the ultimate production of energy through oxidative phosphorylation in mitochondria. Other metabolites such as glucose, amino acids, and ketone bodies come next. Under pathological conditions, there is a shift in metabolic pathways and the preference of metabolites, termed metabolic remodeling or reprogramming. In this review, we aim to summarize cardiovascular metabolism and remodeling in different subsets of CVD to come up with a new paradigm for understanding and treatment of these diseases.

Keywords:  Branched-chain amino acids; Cardiac metabolism; Cardiovascular diseases; Fatty acids; Glucose; Ketone bodies; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12265-023-10432-3
Nat Rev Mol Cell Biol. 2023 Sep 08.

Mechanisms and pathology of protein misfolding and aggregation.

Nikolaos Louros, Joost Schymkowitz, Frederic Rousseau.

Despite advances in machine learning-based protein structure prediction, we are still far from fully understanding how proteins fold into their native conformation. The conventional notion that polypeptides fold spontaneously to their biologically active states has gradually been replaced by our understanding that cellular protein folding often requires context-dependent guidance from molecular chaperones in order to avoid misfolding. Misfolded proteins can aggregate into larger structures, such as amyloid fibrils, which perpetuate the misfolding process, creating a self-reinforcing cascade. A surge in amyloid fibril structures has deepened our comprehension of how a single polypeptide sequence can exhibit multiple amyloid conformations, known as polymorphism. The assembly of these polymorphs is not a random process but is influenced by the specific conditions and tissues in which they originate. This observation suggests that, similar to the folding of native proteins, the kinetics of pathological amyloid assembly are modulated by interactions specific to cells and tissues. Here, we review the current understanding of how intrinsic protein conformational propensities are modulated by physiological and pathological interactions in the cell to shape protein misfolding and aggregation pathology.

DOI: https://doi.org/10.1038/s41580-023-00647-2
Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00643-3. [Epub ahead of print]

eIF3d controls the persistent integrated stress response.

Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee.

  Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.

Keywords:  ATF4; GCN2; RNA methylation; eIF3d; integrated stress response; m(6)A; translation regulation

DOI:  https://doi.org/10.1016/j.molcel.2023.08.008
J Obstet Gynaecol Res. 2023 Sep 08.

The role of mitochondrial dynamics in the pathophysiology of endometriosis.

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

  AIM: Endometriosis is a chronic disease of reproductive age, associated with pelvic pain and infertility. Endometriotic cells adapt to changing environments such as oxidative stress and hypoxia in order to survive. However, the underlying mechanisms remain to be fully elucidated. In this review, we summarize our current understanding of the pathogenesis of endometriosis, focusing primarily on the molecular basis of energy metabolism, redox homeostasis, and mitochondrial function, and discuss perspectives on future research directions.METHODS: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this narrative literature review.
RESULTS: Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production and cellular redox homeostasis. Under hypoxia, endometriotic cells favor glycolysis and actively produce pyruvate, nicotinamide adenine dinucleotide phosphate (NADPH), and other metabolites for cell proliferation. Mitochondrial fission and fusion dynamics may regulate the phenotypic plasticity of cellular energy metabolism, that is, aerobic glycolysis or OXPHOS. Endometriotic cells have been reported to have reduced mitochondrial numbers, increased lamellar cristae, improved energy efficiency, and enhanced cell proliferation and survival. Increased mitochondrial fission and fusion turnover by hypoxic and normoxic conditions suggests an activation of mitochondrial quality control mechanisms. Recently, candidate molecules that influence mitochondrial dynamics have begun to be identified.
CONCLUSION: This review suggests that unique energy metabolism and redox homeostasis driven by mitochondrial dynamics may be linked to the pathophysiology of endometriosis. However, further studies are needed to elucidate the regulatory mechanisms of mitochondrial dynamics in endometriosis.

Keywords:  endometriosis; energy metabolism; mitochondrial dynamics; redox homeostasis

DOI:  https://doi.org/10.1111/jog.15791
Int J Mol Sci. 2023 Sep 04. pii: 13656. [Epub ahead of print]24(17):

Mitochondrial Factors in the Cell Nucleus.

Katiuska González-Arzola, Antonio Díaz-Quintana.

  The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.

Keywords:  DNA damage; hypoxia; mito-nuclear crosstalk; oxidative stress; stress response; unfolded stress response

DOI:  https://doi.org/10.3390/ijms241713656
J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02248-2. [Epub ahead of print] 105220

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.

Wen-Hao Zhou, Yuan Luo, Rui-Xin Li, Pascal Degrace, Tony Jourdan, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Zhen-Yu Du.

  Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mTORC1 activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (Mildronate or Etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through Gcn5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase Gcn5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylases HDAC class II and identified HDAC7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.

Keywords:  Gcn5; Raptor; acetyl-CoA; mTORC1; mitochondrial FAO inhibition

DOI:  https://doi.org/10.1016/j.jbc.2023.105220
J Physiol. 2023 Sep 05.

Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.

Hang Cheng, Guy A Perkins, Saeyeon Ju, Keunyoung Kim, Mark H Ellisman, Matthew E Pamenter.

  Deleterious Ca2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca2+ are retarded in hypoxia-tolerant naked mole-rat brain. We hypothesized that naked mole-rat brain mitochondria have an enhanced capacity to buffer exogenous Ca2+ and examined Ca2+ handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca2+ than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC50 ) at which Ca2+ inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca2+ uptake is the mitochondrial membrane potential (Δψm ), and the IC50 at which Ca2+ decreases Δψm is ∼4-fold higher in naked mole-rat than mouse brain. The ability of naked mole-rat brain mitochondria to safely retain large volumes of Ca2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca2+ in mitochondria. Specifically, and relative to mouse brain, naked mole-rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca2+ management. We propose that excessive Ca2+ influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca2+ overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca2+ influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca2+ influx into naked mole-rat brain is markedly reduced relative to mice. This is important because naked mole-rat brain is robustly tolerant against in vitro hypoxia, and because Ca2+ is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole-rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca2+ stress. This is due to mitochondrial buffering of exogenous Ca2+ and is driven by a mitochondrial membrane potential-dependant mechanism. The unique ultrastructure of naked mole-rat brain mitochondria, as a large physical storage space, may support increased Ca2+ buffering and thus hypoxia-tolerance.

Keywords:  electron transport system; membrane potential; mitochondrial permeability transition pore; oxidative phosphorylation

DOI:  https://doi.org/10.1113/JP285002
Mitochondrion. 2023 Sep 05. pii: S1567-7249(23)00072-7. [Epub ahead of print]

Hypoxia improves self-renew and migration of urine stem cells by upregulating autophagy and mitochondrial function through ERK signal pathway.

Chaoqun Hu, Yanting Sun, Wanxia Li, Yang Bi.

  Urine-derived stem cells (USCs) are autologous stem cells with self-renewal ability and multi-lineage differentiation potential. Our previous studies have shown that hypoxia preconditioning can improve self-renewal and migration abilities of USCs by up-regulating autophagy. The purpose of this study was to investigate the specific mechanism by which hypoxia treatment promotes the biological function of USCs. We found that hypoxia treatment upregulates the expression of phosphralated ERK protein without affecting the expression of total ERK protein. Inhibiting ERK signaling with the PD98059 inhibitor decreased cell proliferation, migration and colony formation during hypoxia treatment. Hypoxia increased ATP production, mitochondrial membrane potential and mt-DNA copy number, which were reversed by inhibiting the ERK signal. Additionally, the number of autophagosomes and autophagic lysosomes was significantly lower in PD98059 group than in the hypoxia group. PD98059 treatment inhibited the up-regulation of autophagy related proteins induced by hypoxia. Therefore, this study suggests that hypoxia improves the self-renewal and migration abilities of USCs by upregulating autophagy and mitochondrial function through ERK signaling pathway. This finding may provide a new therapeutic mechanism for hypoxia pretreated USCs as a source of stem cell transplantation.

Keywords:  ERK signal pathway; Urine-derived stem cells; autophagy; hypoxia; mitochondrial function

DOI:  https://doi.org/10.1016/j.mito.2023.09.001
J Alzheimers Dis. 2023 Aug 25.

Circulating Exosomes from Alzheimer's Disease Suppress Vascular Endothelial-Cadherin Expression and Induce Barrier Dysfunction in Recipient Brain Microvascular Endothelial Cell.

Jiani Bei, Ernesto G Miranda-Morales, Qini Gan, Yuan Qiu, Sorosh Husseinzadeh, Jia Yi Liew, Qing Chang, Balaji Krishnan, Angelo Gaitas, Subo Yuan, Michelle Felicella, Wei Qiao Qiu, Xiang Fang, Bin Gong.

  BACKGROUND: Blood-brain barrier (BBB) breakdown is a crucial aspect of Alzheimer's disease (AD) progression. Dysfunction in BBB is primarily caused by impaired tight junction and adherens junction proteins in brain microvascular endothelial cells (BMECs). The role of adherens junctions in AD-related BBB dysfunction remains unclear. Exosomes from senescent cells have unique characteristics and contribute to modulating the phenotype of recipient cells. However, it remains unknown if and how these exosomes cause BMEC dysfunction in AD.OBJECTIVE: This study aimed to investigate the impact of AD circulating exosomes on brain endothelial dysfunction.
METHODS: Exosomes were isolated from sera of AD patients and age- and sex-matched cognitively normal controls using size-exclusion chromatography. The study measured the biomechanical nature of BMECs' endothelial barrier, the lateral binding forces between live BMECs. Paracellular expressions of the key adherens junction protein vascular endothelial (VE)-cadherin were visualized in BMEC cultures and a 3D BBB model using human BMECs and pericytes. VE-cadherin signals were also examined in brain tissues from AD patients and normal controls.
RESULTS: Circulating exosomes from AD patients reduced VE-cadherin expression levels and impaired barrier function in recipient BMECs. Immunostaining analysis demonstrated that AD exosomes damaged VE-cadherin integrity in a 3D microvascular tubule formation model. The study found that AD exosomes weakened BBB integrity depending on their RNA content. Additionally, diminished microvascular VE-cadherin expression was observed in AD brains compared to controls.
CONCLUSION: These findings highlight the significant role of circulating exosomes from AD patients in damaging adherens junctions of recipient BMECs, dependent on exosomal RNA.

Keywords:  3D microvascular model; Alzheimer’s disease; VE-cadherin ; blood-brain barrier; endothelial barrier dysfunction; exosome; fluidic AFM

DOI:  https://doi.org/10.3233/JAD-230347