bims-midtic 2023-12-03 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒12‒03
thirty papers selected by
Omkar Joshi, Turku Bioscience

Review title: Mechanisms of mitochondrial reorganization.
Biased placement of Mitochondria fission facilitates asymmetric inheritance of protein aggregates during yeast cell division.
Effects of phosphorylation on Drp1 activation by its receptors, actin, and cardiolipin.
TGF-β3 mediates mitochondrial dynamics through the p-Smad3/AMPK pathway.
Mitochondrial quality control in health and cardiovascular diseases.
Restoring the infected powerhouse: Mitochondrial quality control in sepsis.
Protocol for evaluating mitochondrial morphology changes in response to CCCP-induced stress through open-source image processing software.
Metabolic control of mitophagy.
Thioflavin T indicates mitochondrial membrane potential in mammalian cells.
Osteopontin induces mitochondrial biogenesis in deadherent cancer cells.
The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
In vitro anticancer effect of azithromycin targeting hypoxic lung cancer cells via the inhibition of mitophagy.
Basal activity of PINK1 and PRKN in cell models and rodent brain.
Melittin kills A549 cells by targeting mitochondria and blocking mitophagy flux.
The subset of peroxisomal tail-anchored proteins do not reach peroxisomes via ER, instead mitochondria can be involved.
O-GlcNAcylation is essential for therapeutic mitochondrial transplantation.
Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy via Inhibition of Mitochondrial Fission.
Nanojunctions: Specificity of Ca2+ signaling requires nano-scale architecture of intracellular membrane contact sites.
Decoding mitochondrial-nuclear (epi)genome interactions: the emerging role of ncRNAs.
Role of F-actin-mediated endocytosis and exercise in mitochondrial transplantation in an experimental Parkinson's disease mouse model.
Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.
Ca2+ concentrations in mouse sperm mitochondria fluctuate according to the cytosol.
Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.
Mitophagy in human health, ageing and disease.
Dexmedetomidine ameliorates high glucose-induced epithelial-mesenchymal transformation in HK-2 cells through the Cdk5/Drp1/ROS pathway.
Mitochondria as a sensor, a central hub and a biological clock in psychological stress-accelerated aging.
Mitochondrial Dysfunction in Kidney Tubulopathies.
Temporally multiplexed imaging of dynamic signaling networks in living cells.
HIF-1α-Induced Mitophagy Regulates the Regenerative Outcomes of Stem Cells in Fat Transplantation.
Regular exercise attenuates alcoholic myopathy in zebrafish by modulating mitochondrial homeostasis.

J Biochem. 2023 Nov 28. pii: mvad098. [Epub ahead of print]

Review title: Mechanisms of mitochondrial reorganization.

Tatsuro Maruyama, Yutaro Hama, Nobuo N Noda.

  The cytoplasm of eukaryotes is dynamically zoned by membrane-bound and membraneless organelles. Cytoplasmic zoning allows various biochemical reactions to take place at the right time and place. Mitochondrion is a membrane-bound organelle that provides a zone for intracellular energy production and metabolism of lipids and iron. A key feature of mitochondria is their high dynamics: mitochondria constantly undergo fusion and fission, and excess or damaged mitochondria are selectively eliminated by mitophagy. Therefore, mitochondria are appropriate model systems to understand dynamic cytoplasmic zoning by membrane organelles. In this review, we summarize the molecular mechanisms of mitochondrial fusion and fission as well as mitophagy unveiled through studies using yeast and mammalian models.

Keywords:  cytoplasmic zoning; mitochondria; mitochondrial fission; mitochondrial fusion; mitophagy

DOI:  https://doi.org/10.1093/jb/mvad098
PLoS Comput Biol. 2023 Nov 27. 19(11): e1011588

Biased placement of Mitochondria fission facilitates asymmetric inheritance of protein aggregates during yeast cell division.

Gordon Sun, Christine Hwang, Tony Jung, Jian Liu, Rong Li.

Mitochondria are essential and dynamic eukaryotic organelles that must be inherited during cell division. In yeast, mitochondria are inherited asymmetrically based on quality, which is thought to be vital for maintaining a rejuvenated cell population; however, the mechanisms underlying mitochondrial remodeling and segregation during this process are not understood. We used high spatiotemporal imaging to quantify the key aspects of mitochondrial dynamics, including motility, fission, and fusion characteristics, upon aggregation of misfolded proteins in the mitochondrial matrix. Using these measured parameters, we developed an agent-based stochastic model of dynamics of mitochondrial inheritance. Our model predicts that biased mitochondrial fission near the protein aggregates facilitates the clustering of protein aggregates in the mitochondrial matrix, and this process underlies asymmetric mitochondria inheritance. These predictions are supported by live-cell imaging experiments where mitochondrial fission was perturbed. Our findings therefore uncover an unexpected role of mitochondrial dynamics in asymmetric mitochondrial inheritance.

DOI: https://doi.org/10.1371/journal.pcbi.1011588
Mol Biol Cell. 2023 Nov 29. mbcE23110427

Effects of phosphorylation on Drp1 activation by its receptors, actin, and cardiolipin.

Ao Liu, Anna L Hatch, Henry N Higgs.

Drp1 is a dynamin family GTPase required for mitochondrial and peroxisomal division. Oligomerization increases Drp1 GTPase activity through interactions between neighboring GTPase domains. In cells, Drp1 is regulated by several factors including Drp1 receptors, actin filaments, cardiolipin, and phosphorylation at two sites: S579 and S600. Commonly, phosphorylation of S579 is considered activating, while S600 phosphorylation is considered inhibiting. However, direct effects of phosphorylation on Drp1 GTPase activity have not been investigated in detail. Here, we compare effects of S579 and S600 phosphorylation on purified Drp1, using phospho-mimetic mutants and in vitro phosphorylation. Both phospho-mimetic mutants are shifted toward smaller oligomers. Both phospho-mimetic mutations maintain basal GTPase activity, but eliminate GTPase stimulation by actin and decrease GTPase stimulation by cardiolipin, Mff, and MiD49. Phosphorylation of S579 by Erk2 produces similar effects. When mixed with wildtype Drp1, both S579D and S600D phospho-mimetic mutants reduce the actin-stimulated GTPase activity of Drp1-WT. Conversely, a Drp1 mutant (K38A) lacking GTPase activity stimulates Drp1-WT GTPase activity under both basal and actin-stimulated conditions. These results suggest that the effect of S579 phosphorylation is not to activate Drp1 directly. In addition, our results suggest that nearest neighbor interactions within the Drp1 oligomer affect catalytic activity.

DOI: https://doi.org/10.1091/mbc.E23-11-0427
Cell Prolif. 2023 Nov 27. e13579

TGF-β3 mediates mitochondrial dynamics through the p-Smad3/AMPK pathway.

Xinmei Du, Mengmeng Duan, Shiyi Kan, Yueyi Yang, Siqun Xu, Jieya Wei, Jiazhou Li, Hao Chen, Xuedong Zhou, Jing Xie.

It is well recognized that mitochondrial dynamics plays a vital role in cartilage physiology. Any perturbation in mitochondrial dynamics could cause disorders in cartilage metabolism and even lead to the occurrence of cartilage diseases such as osteoarthritis (OA). TGF-β3, as an important growth factor that appears in the joints of OA disease, shows its great potential in chondrocyte growth and metabolism. Nevertheless, the role of TGF-β3 on mitochondrial dynamics is still not well understood. Here we aimed to investigate the effect of TGF-β3 on mitochondrial dynamics of chondrocytes and reveal its underlying bio-mechanism. By using transmission electron microscopy (TEM) for the number and morphology of mitochondria, western blotting for the protein expressions, immunofluorescence for the cytoplasmic distributions of proteins, and RNA sequencing for the transcriptome changes related to mitochondrial dynamics. We found that TGF-β3 could increase the number of mitochondria in chondrocytes. TGF-β3-enhanced mitochondrial number was via promoting the mitochondrial fission. The mitochondrial fission induced by TGF-β3 was mediated by AMPK signaling. TGF-β3 activated canonical p-Smad3 signaling and resultantly mediated AMPK-induced mitochondrial fission. Taken together, these results elucidate an understanding of the role of TGF-β3 on mitochondrial dynamics in chondrocytes and provide potential cues for therapeutic strategies in cartilage injury and OA disease in terms of energy metabolism.

DOI: https://doi.org/10.1111/cpr.13579
Front Cell Dev Biol. 2023 ;11 1290046

Mitochondrial quality control in health and cardiovascular diseases.

Asli E Atici, Timothy R Crother, Magali Noval Rivas.

  Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.

Keywords:  ROS; cardiovascular disease; mitobiogenesis; mitochondria; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.3389/fcell.2023.1290046
Redox Biol. 2023 Nov 23. pii: S2213-2317(23)00369-5. [Epub ahead of print]68 102968

Restoring the infected powerhouse: Mitochondrial quality control in sepsis.

F M Lira Chavez, L P Gartzke, F E van Beuningen, S E Wink, R H Henning, G Krenning, H R Bouma.

  Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria fulfil dual roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function but also influence inflammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual impact, compromising both immune system efficiency and the metabolic stability of end organs. Dysfunctional mitochondria contribute to the development of a hyperinflammatory state and loss of cellular homeostasis, resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mitochondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria. However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mitochondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facilitate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis, specifically mitophagy, and the optimal timing for intervention remain poorly understood. This review emphasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects associated with solely the induction of mitochondrial biogenesis.

Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Sepsis

DOI:  https://doi.org/10.1016/j.redox.2023.102968
STAR Protoc. 2023 Nov 29. pii: S2666-1667(23)00712-8. [Epub ahead of print]4(4): 102745

Protocol for evaluating mitochondrial morphology changes in response to CCCP-induced stress through open-source image processing software.

Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.

  Mitochondrial morphology is an indicator of cellular health and function; however, its quantification and categorization into different subclasses is a complicated process. Here, we present a protocol for mitochondrial morphology quantification in the presence and absence of carbonyl cyanide m-chlorophenyl hydrazone stress. We describe steps for the preparation of cells for immunofluorescence microscopy, staining, and morphology quantification. The quantification protocol generates an aspect ratio that helps to categorize mitochondria into two clear subclasses. For complete details on the use and execution of this protocol, please refer to Nag et al.1.

Keywords:  Cell Biology; Cell culture; Metabolism; Microscopy; Molecular/Chemical Probes

DOI:  https://doi.org/10.1016/j.xpro.2023.102745
Eur J Clin Invest. 2023 Dec 01. e14138

Metabolic control of mitophagy.

Andreas Zimmermann, Frank Madeo, Abhinav Diwan, Junichi Sadoshima, Simon Sedej, Guido Kroemer, Mahmoud Abdellatif.

  Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP-dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria-associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill-defined distinction between basal and damage-induced mitophagy, which must be resolved to boost progress in this area.

Keywords:  AMPK; NAD; acetyl-CoA; ageing; ageing-related disease; metabolism; mitophagy; spermidine

DOI:  https://doi.org/10.1111/eci.14138
Biophys Rep (N Y). 2023 Dec 13. 3(4): 100134

Thioflavin T indicates mitochondrial membrane potential in mammalian cells.

Emily Skates, Hadrien Delattre, Zoe Schofield, Munehiro Asally, Orkun S Soyer.

The fluorescent benzothiazole dye thioflavin T (ThT) is widely used as a marker for protein aggregates, most commonly in the context of neurodegenerative disease research and diagnosis. Recently, this same dye was shown to indicate membrane potential in bacteria due to its cationic nature. This finding prompted a question whether ThT fluorescence is linked to the membrane potential in mammalian cells, which would be important for appropriate utilization of ThT in research and diagnosis. Here, we show that ThT localizes into the mitochondria of HeLa cells in a membrane-potential-dependent manner. Specifically, ThT colocalized in cells with the mitochondrial membrane potential indicator tetramethylrhodamine methyl ester (TMRM) and gave similar temporal responses as TMRM to treatment with a protonophore, carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP). Additionally, we found that presence of ThT together with exposure to blue light (λ = 405 nm), but neither factor alone, caused depolarization of mitochondrial membrane potential. This additive effect of the concentration and blue light was recapitulated by a mathematical model implementing the potential-dependent distribution of ThT and its effect on mitochondrial membrane potential through photosensitization. These results show that ThT can act as a mitochondrial membrane potential indicator in mammalian cells, when used at low concentrations and with low blue light exposure. However, it causes dissipation of the mitochondrial membrane potential depending additively on its concentrations and blue light exposure. This conclusion motivates a re-evaluation of ThT's use at micromolar range in live-cell analyses and indicates that this dye can enable future studies on the potential connections between mitochondrial membrane potential dynamics and protein aggregation.

DOI: https://doi.org/10.1016/j.bpr.2023.100134
Oncotarget. 2023 Dec 01. 14 957-969

Osteopontin induces mitochondrial biogenesis in deadherent cancer cells.

Gulimirerouzi Fnu, Georg F Weber.

  Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms. Here, we report that autocrine Osteopontin does indeed stimulate an increase in mitochondrial size, with the splice variant -c being more effective than the full-length form -a. Osteopontin-c achieves this via its receptor CD44v, jointly with the upregulation and co-ligation of the chloride-dependent cystine-glutamate transporter SLC7A11. The signaling proceeds through activation of the known mitochondrial biogenesis inducer PGC-1 (which acts as a transcription coactivator). Peroxide is an important intermediate in this cascade, but surprisingly acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation. In vivo, suppression of the biogenesis-inducing mechanisms leads to a reduction in disseminated tumor mass. This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis - both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.

Keywords:  anchorage independence; metabolism; metastasis; mitochondrial mass; peroxide

DOI:  https://doi.org/10.18632/oncotarget.28540
Nat Commun. 2023 Nov 30. 14(1): 7889

The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.

Nathan Meade, Helen K Toreev, Ram P Chakrabarty, Charles R Hesser, Chorong Park, Navdeep S Chandel, Derek Walsh.

Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.

DOI: https://doi.org/10.1038/s41467-023-43635-y
Oncol Lett. 2024 Jan;27(1): 12

In vitro anticancer effect of azithromycin targeting hypoxic lung cancer cells via the inhibition of mitophagy.

Kazutoshi Toriyama, Takashi Okuma, Shinji Abe, Hiroyuki Nakamura, Kazutetsu Aoshiba.

  Solid tumors are predisposed to hypoxia, which induces tumor progression, and causes resistance to treatment. Hypoxic tumor cells exploit auto- and mitophagy to facilitate metabolism and mitochondrial renewal. Azithromycin (AZM), a widely used macrolide, inhibits autophagy in cancer cells. The aim of the present study was to determine whether AZM targeted hypoxic cancer cells by inhibiting mitophagy. Lung cancer cell lines (A549, H1299 and NCI-H441) were cultured for up to 72 h under normoxic (20% O2) or hypoxic (0.3% O2) conditions in the presence or absence of AZM (≤25 µM), and the cell survival, autophagy flux and mitophagy flux were evaluated. AZM treatment reduced cell survival under hypoxic conditions, caused mitolysosome dysfunction with raised lysosomal pH and impaired the efficient removal of hypoxia-damaged mitochondria, eventually inducing apoptosis in the cancer cells. The cytotoxic effect of AZM under hypoxic conditions was abolished in mitochondria-deficient A549 cells (ρ° cells). The present study demonstrated that AZM reduced lung cancer cell survival under hypoxic conditions by interfering with the efficient removal of damaged mitochondria through mitophagy inhibition. Thus, AZM may be considered as a promising anticancer drug that targets the mitochondrial vulnerability of hypoxic lung cancer cells.

Keywords:  AZM; TME; autophagy; hypoxia; mitophagy

DOI:  https://doi.org/10.3892/ol.2023.14146
Autophagy. 2023 Dec 02. 1-12

Basal activity of PINK1 and PRKN in cell models and rodent brain.

Jens O Watzlawik, Fabienne C Fiesel, Gabriella Fiorino, Bernardo A Bustillos, Zahra Baninameh, Briana N Markham, Xu Hou, Caleb S Hayes, Jenny M Bredenberg, Nicholas W Kurchaba, Dominika Fričová, Joanna Siuda, Zbigniew K Wszolek, Sachiko Noda, Shigeto Sato, Nobutaka Hattori, Asheeta A Prasad, Deniz Kirik, Howard S Fox, Kelly L Stauch, Matthew S Goldberg, Wolfdieter Springer.

  The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.

Keywords:  Mitophagy; PINK1; PRKN; Parkinson disease; parkin; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2023.2286414
Redox Rep. 2023 Dec;28(1): 2284517

Melittin kills A549 cells by targeting mitochondria and blocking mitophagy flux.

Xuan Li, Zheng Li, Yu-Qi Meng, Hui Qiao, Ke-Rong Zhai, Zhen-Qing Li, Shi-Lin Wei, Bin Li.

  Melittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells.

Keywords:  A549 cells; Melittin; ROS; apoptosis; autophagy; mitochondria damage; mitophagy; mitophagy flux

DOI:  https://doi.org/10.1080/13510002.2023.2284517
PLoS One. 2023 ;18(12): e0295047

The subset of peroxisomal tail-anchored proteins do not reach peroxisomes via ER, instead mitochondria can be involved.

Tamara Somborac, Güleycan Lutfullahoglu Bal, Kaneez Fatima, Helena Vihinen, Anja Paatero, Eija Jokitalo, Ville O Paavilainen, Svetlana Konovalova.

Peroxisomes are membrane-enclosed organelles with important roles in fatty acid breakdown, bile acid synthesis and biosynthesis of sterols and ether lipids. Defects in peroxisomes result in severe genetic diseases, such as Zellweger syndrome and neonatal adrenoleukodystrophy. However, many aspects of peroxisomal biogenesis are not well understood. Here we investigated delivery of tail-anchored (TA) proteins to peroxisomes in mammalian cells. Using glycosylation assays we showed that peroxisomal TA proteins do not enter the endoplasmic reticulum (ER) in both wild type (WT) and peroxisome-lacking cells. We observed that in cells lacking the essential peroxisome biogenesis factor, PEX19, peroxisomal TA proteins localize mainly to mitochondria. Finally, to investigate peroxisomal TA protein targeting in cells with fully functional peroxisomes we used a proximity biotinylation approach. We showed that while ER-targeted TA construct was exclusively inserted into the ER, peroxisome-targeted TA construct was inserted to both peroxisomes and mitochondria. Thus, in contrast to previous studies, our data suggest that some peroxisomal TA proteins do not insert to the ER prior to their delivery to peroxisomes, instead, mitochondria can be involved.

DOI: https://doi.org/10.1371/journal.pone.0295047
Commun Med (Lond). 2023 Nov 25. 3(1): 169

O-GlcNAcylation is essential for therapeutic mitochondrial transplantation.

Ji Hyun Park, Masayoshi Tanaka, Takafumi Nakano, Ester Licastro, Yoshihiko Nakamura, Wenlu Li, Elga Esposito, Emiri T Mandeville, Sherry Hsiang-Yi Chou, MingMing Ning, Eng H Lo, Kazuhide Hayakawa.

BACKGROUND: Transplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfavorable danger signals.METHODS: Mitochondrial O-GlcNAc-modification was amplified by recombinant O-GlcNAc transferase (OGT) and UDP-GlcNAc. O-GlcNAcylated mitochondrial proteins were identified by mass spectrometry and the antiglycation ability of O-GlcNAcylated DJ1 was determined by loss-of-function via mutagenesis. Therapeutic efficacy of O-GlcNAcylated mitochondria was assessed in a mouse model of transient focal cerebral ischemia-reperfusion. To explore translational potential, we evaluated O-GlcNAcylated DJ1 in CSF collected from patients with subarachnoid hemorrhagic stroke (SAH).
RESULTS: We show that isolated mitochondria are susceptible to advanced glycation end product (AGE) modification, and these glycated mitochondria induce the receptor for advanced glycation end product (RAGE)-mediated autophagy and oxidative stress when transferred into neurons. However, modifying mitochondria with O-GlcNAcylation counteracts glycation, diminishes RAGE-mediated effects, and improves viability of mitochondria recipient neurons. In a mouse model of stroke, treatment with extracellular mitochondria modified by O-GlcNAcylation reduces neuronal injury and improves neurologic deficits. In cerebrospinal fluid (CSF) samples from SAH patients, levels of O-GlcNAcylation in extracellular mitochondria correlate with better clinical outcomes.
CONCLUSIONS: These findings suggest that AGE-modification in extracellular mitochondria may induce danger signals, but O-GlcNAcylation can prevent glycation and improve the therapeutic efficacy of transplanted mitochondria in the CNS.

DOI: https://doi.org/10.1038/s43856-023-00402-w
J Cardiovasc Pharmacol. 2023 Nov 22.

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy via Inhibition of Mitochondrial Fission.

Zhuo-Jing Yang, Chun-Ling Guo, Yu-Xin Gong, Long Li, Li-Li Wang, Hui-Min Liu, Ji-Min Cao, Zhao-Yang Lu.

ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for two weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum (IVS), left ventricle posterior wall diastole (LVPWd) and left ventricular posterior wall systole (LVPWs) were significantly increased, and ejection fraction (EF) was decreased compared with control mice. Masson and Wheat Germ Agglutinin (WGA) staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes (NRCMs), we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and NRCMs. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase Drp1 phosphorylation at S616 and decrease Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.

DOI: https://doi.org/10.1097/FJC.0000000000001518
Cell Calcium. 2023 Nov 19. pii: S0143-4160(23)00148-3. [Epub ahead of print]117 102837

Nanojunctions: Specificity of Ca2+ signaling requires nano-scale architecture of intracellular membrane contact sites.

Nicola Fameli, Cornelis van Breemen, Klaus Groschner.

  Spatio-temporal definition of Ca2+ signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic reticulum (SR/ER) and the plasma membrane (PM). While the requirement of precise spatial assembly and positioning of the junctional signaling elements is well documented, the role of the nano-scale membrane architecture itself, as an ion-reflecting confinement of the signalling unit, remains as yet elusive. Utilizing the Na+/Ca2+ Exchanger-1 / SR/ER Ca2+ ATPase-2-mediated ER Ca2+ refilling process as a junctional signalling paradigm, we provide here the first evidence for an indispensable cellular function of the junctional membrane architecture. Our stochastic modeling approach demonstrates that junctional ER Ca2+ refilling operates exclusively at nano-scale membrane spacing, with a strong inverse relationship between junctional width and signaling efficiency. Our model predicts a breakdown of junctional Ca2+ signaling with loss of reflecting membrane confinement. In addition we consider interactions between Ca2+ and the phospholipid membrane surface, which may support interfacial Ca2+ transport and promote receptor targeting. Alterations in the molecular and nano-scale membrane organization at organelle-PM contacts are suggested as a new concept in pathophysiology.

Keywords:  Calcium signalling; Computational simulation; Na(+)/Ca(2+) exchanger; Nanojunctions; PM-ER junctions; Stochastic model

DOI:  https://doi.org/10.1016/j.ceca.2023.102837
Epigenomics. 2023 Nov;15(21): 1121-1136

Decoding mitochondrial-nuclear (epi)genome interactions: the emerging role of ncRNAs.

Julia Nguyen, Quinn Le, Phyo W Win, Kathleen A Hill, Shiva M Singh, Christina A Castellani.

  Bidirectional communication between the mitochondria and the nucleus is required for several physiological processes, and the nuclear epigenome is a key mediator of this relationship. ncRNAs are an emerging area of discussion for their roles in cellular function and regulation. In this review, we highlight the role of mitochondrial-encoded ncRNAs as mediators of communication between the mitochondria and the nuclear genome. We focus primarily on retrograde signaling, a process in which the mitochondrion relays ncRNAs to translate environmental stress signals to changes in nuclear gene expression, with implications on stress responses that may include disease(s). Other biological roles of mitochondrial-encoded ncRNAs, such as mitochondrial import of proteins and regulation of cell signaling, will also be discussed.

Keywords:  disease risk; gene expression; mitochondria; ncRNA; retrograde signaling

DOI:  https://doi.org/10.2217/epi-2023-0322
Mitochondrion. 2023 Nov 29. pii: S1567-7249(23)00095-8. [Epub ahead of print]

Role of F-actin-mediated endocytosis and exercise in mitochondrial transplantation in an experimental Parkinson's disease mouse model.

Rachit Jain, Nusrat Begum, Shruti Rajan, Kamatham Pushpa Tryphena, Dharmendra Kumar Khatri.

  Dopaminergic neurons gradually deteriorate in Parkinson's Disease (PD), which is characterized by the intracellular accumulation of Lewy bodies that are enriched with α-synuclein protein. Mitochondrial dysfunction is one of the primary contributors to this and is considered as the central player in the pathogenesis of PD. Recently, improving mitochondrial function has been extensively explored as a therapeutic strategy in various preclinical PD models. Mitochondrial transplantation is one such naïve yet highly efficient technique that has been well explored in diseases like diabetes, NAFLD, and cardiac ischemia but not in PD. Here, we compared the effects of transplanting normal allogenic mitochondria to those of transplanting exercise-induced allogenic mitochondria isolated from the liver into the PD mouse model. It is already known that normal Mitochondrial Transplant (MT) reduces the PD pathology, but our research found out that exercise-induced mitochondria were more effective in treating the PD pathology because they had higher respiratory capacities. Additionally, compared to a standard transplant, this therapy significantly boosted the rate of mitochondrial biogenesis and the quantity of mitochondrial subunits in PD mice. Further, we also explored the mechanism of mitochondrial uptake into the cells and found that F-actin plays a key role in the internalization of mitochondria. This study is the first to demonstrate the relevance of exercise-induced allogenic MT and the function of F-actin in the internalization of mitochondria in PD mice.

Keywords:  Exercise; F-actin; Mitochondria; Mitochondrial Transplant; Parkinson’s Disease

DOI:  https://doi.org/10.1016/j.mito.2023.11.007
Mol Neurobiol. 2023 Nov 28.

Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.

Ranita Ghosh Dastidar, Saradindu Banerjee, Piyush Behari Lal, Somasish Ghosh Dastidar.

  AFG3L2 is a zinc metalloprotease and an ATPase localized in an inner mitochondrial membrane involved in mitochondrial quality control of several nuclear- and mitochondrial-encoded proteins. Mutations in AFG3L2 lead to diseases like slow progressive ataxia, which is a neurological disorder. This review delineates the cellular functions of AFG3L2 and its dysfunction that leads to major clinical outcomes, which include spinocerebellar ataxia type 28, spastic ataxia type 5, and optic atrophy type 12. It summarizes all relevant AFG3L2 mutations associated with the clinical outcomes to understand the detailed mechanisms attributable to its structure-related multifaceted roles in proteostasis and quality control. We face early diagnostic challenges of ataxia and optic neuropathy due to asymptomatic parents and variable clinical manifestations due to heterozygosity/homozygosity of AFG3L2 mutations. This review intends to promote AFG3L2 as a putative prognostic or diagnostic marker. Functions, mutations, and clinical manifestations in AFG3L2, a mitochondrial AAA + ATPases.

Keywords:  AFG3L2; Ataxia; Mitochondria; Neurological disorders; SCA28; Zinc metalloprotease

DOI:  https://doi.org/10.1007/s12035-023-03768-z
Reproduction. 2023 Dec 01. pii: REP-23-0237. [Epub ahead of print]

Ca2+ concentrations in mouse sperm mitochondria fluctuate according to the cytosol.

Yoloxochitl Sánchez-Guevara, Enrique I Oliver, Takuya Nishigaki.

Mitochondria are important organelles in eukaryotic cells and play an essential role in energy production and cell signaling. However, the importance of mammalian sperm mitochondria as an energy source remains to be elucidated because glycolysis is known to be dominant. In this context, one of the functions of mammalian sperm mitochondria is considered as a calcium ion (Ca2+) homeostasis. Previously, the Ca2+ level within the mitochondria of mouse sperm under resting conditions was reported to be high (in the micromolar range) using the fluorescent Ca2+ indicator Calcium Green-5N (CG-5N). To confirm this fact, we performed the semi-quantitative determination of Ca2+ concentration with several Ca2+ indicators. Although we reproduced the previous report of CG-5N, other Ca2+ indicators do not support the result obtained with CG-5N. The results obtained with Rhod-2, Fluo-3, and Fluo-5N indicate that the free Ca2+ concentration in mitochondria is comparable to that of the cytosol at the resting condition and under the condition stimulated by ATP. Although we still do not understand why CG-5N exhibits a distinct result from other indicators, the regulation of Ca2+ concentration in murine sperm mitochondria is analogous to that observed in somatic cells. Namely, the Ca2+ concentrations within sperm mitochondria fluctuate in response to changes in cytosolic Ca2+ levels. Our results contribute to a revised understanding of the role of mitochondria in Ca2+ homeostasis in mammalian sperm.

DOI: https://doi.org/10.1530/REP-23-0237
Cell Mol Life Sci. 2023 Nov 25. 80(12): 373

Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.

Federica Rizzo, Silvia Bono, Marc David Ruepp, Sabrina Salani, Linda Ottoboni, Elena Abati, Valentina Melzi, Chiara Cordiglieri, Serena Pagliarani, Roberta De Gioia, Alessia Anastasia, Michela Taiana, Manuela Garbellini, Simona Lodato, Paolo Kunderfranco, Daniele Cazzato, Daniele Cartelli, Caterina Lonati, Nereo Bresolin, Giacomo Comi, Monica Nizzardo, Stefania Corti.

  Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing cDNA encoding functional MFN2 modified to be resistant to RNAi. We tested this strategy in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), demonstrating the correct silencing of endogenous MFN2 and replacement with an exogenous copy of the functional wild-type gene. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. The MFN2 molecular correction was also properly confirmed in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs into newborn mice using adeno-associated virus 9 (AAV9). Altogether, our data support the feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with MFN2 mutations.

Keywords:  CMT2A; Gene therapy; MFN2; MitoCharc1; Motor neuron; RNA interfering

DOI:  https://doi.org/10.1007/s00018-023-05018-w
Nat Metab. 2023 Nov 30.

Mitophagy in human health, ageing and disease.

Anna Picca, Julie Faitg, Johan Auwerx, Luigi Ferrucci, Davide D'Amico.

Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.

DOI: https://doi.org/10.1038/s42255-023-00930-8
Acta Biochim Biophys Sin (Shanghai). 2023 Nov 27.

Dexmedetomidine ameliorates high glucose-induced epithelial-mesenchymal transformation in HK-2 cells through the Cdk5/Drp1/ROS pathway.

Fei Wang, Weilong Xu, Xiaoge Liu, Jun Zhang.

  Epithelial-mesenchymal transformation (EMT) plays an important role in the progression of diabetic nephropathy. Dexmedetomidine (DEX) has shown renoprotective effects against ischemic reperfusion injury; however, whether and how DEX prevents high glucose-induced EMT in renal tubular epithelial cells is incompletely known. Here, we conduct in vitro experiments using HK-2 cells, a human tubular epithelial cell line. Our results demonstrate that high glucose increases the expressions of EMT-related proteins, including Vimentin, Slug, Snail and Twist, while decreasing the expression of E-cadherin and increasing Cdk5 expression in HK-2 cells. Both Cdk5 knockdown and inhibition by roscovitine increase the expressions of E-cadherin while decreasing the expressions of other EMT-related markers. DEX inhibits Cdk5 expression without affecting cell viability and changes the expressions of EMT-related markers, similar to effects of Cdk5 inhibition. Furthermore, Cdk5 is found to interact with Drp1 at the protein level and mediate the phosphorylation of Drp1. In addition, Drp1 inhibition with mdivi-1 could also restrain the high glucose-induced EMT process in HK-2 cells. Immunofluorescence results show that roscovitine, Mdivi-1 and DEX inhibit high glucose-induced intracellular ROS accumulation, while the oxidant H 2O 2 eliminates the protective effect of DEX on the EMT process. These results indicate that DEX mitigates high glucose-induced EMT progression in HK-2 cells via inhibition of the Cdk5/Drp1/ROS pathway.

Keywords:  cyclin-dependent kinase 5; dexmedetomidine; dynamin-related protein 1; epithelial-mesenchymal transformation; high glucose

DOI:  https://doi.org/10.3724/abbs.2023220
Ageing Res Rev. 2023 Nov 27. pii: S1568-1637(23)00304-5. [Epub ahead of print] 102145

Mitochondria as a sensor, a central hub and a biological clock in psychological stress-accelerated aging.

Xuyun Liu, Xing Zhang, Lin Zhao, Jiangang Long, Zhihui Feng, Jiacan Su, Feng Gao, Jiankang Liu.

  The theory that oxidative damage caused by mitochondrial free radicals leads to aging has brought mitochondria into the forefront of aging research. Psychological stress that encompasses many different experiences and exposures across the lifespan has been identified as a catalyst for accelerated aging. Mitochondria, known for their dynamic nature and adaptability, function as a highly sensitive stress sensor and central hub in the process of accelerated aging. In this review, we explore how mitochondria as sensors respond to psychological stress and contribute to the molecular processes in accelerated aging by viewing mitochondria as hormonal, mechanosensitive and immune suborganelles. This understanding of the key role played by mitochondria and their close association with accelerated aging helps us to distinguish normal aging from accelerated aging, correct misconceptions in aging studies, and develop strategies such as exercise and mitochondria-targeted nutrients and drugs for slowing down accelerated aging, and also hold promise for prevention and treatment of age-related diseases.

Keywords:  Accelerated aging; Hormonal sensor; Inflammation; Mechanosensor; Mitochondria; Psychological stress

DOI:  https://doi.org/10.1016/j.arr.2023.102145
Annu Rev Physiol. 2023 Nov 27.

Mitochondrial Dysfunction in Kidney Tubulopathies.

Charlotte A Hoogstraten, Joost G Hoenderop, Jeroen H F de Baaij.

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-042222-025000
Cell. 2023 Nov 21. pii: S0092-8674(23)01227-8. [Epub ahead of print]

Temporally multiplexed imaging of dynamic signaling networks in living cells.

Yong Qian, Orhan T Celiker, Zeguan Wang, Burcu Guner-Ataman, Edward S Boyden.

  Molecular signals interact in networks to mediate biological processes. To analyze these networks, it would be useful to image many signals at once, in the same living cell, using standard microscopes and genetically encoded fluorescent reporters. Here, we report temporally multiplexed imaging (TMI), which uses genetically encoded fluorescent proteins with different clocklike properties-such as reversibly photoswitchable fluorescent proteins with different switching kinetics-to represent different cellular signals. We linearly decompose a brief (few-second-long) trace of the fluorescence fluctuations, at each point in a cell, into a weighted sum of the traces exhibited by each fluorophore expressed in the cell. The weights then represent the signal amplitudes. We use TMI to analyze relationships between different kinase activities in individual cells, as well as between different cell-cycle signals, pointing toward broad utility throughout biology in the analysis of signal transduction cascades in living systems.

Keywords:  TMI; cell cycle; cytoskeleton; fluorescent indicators; fluorescent proteins; live-cell imaging; microscopy; organelle; protein kinase; signal transduction; temporally multiplexed imaging

DOI:  https://doi.org/10.1016/j.cell.2023.11.010
Cell Transplant. 2023 Jan-Dec;32:32 9636897231210750

HIF-1α-Induced Mitophagy Regulates the Regenerative Outcomes of Stem Cells in Fat Transplantation.

Kai Zhang, Dan Jin, Xin Zhao, Bin Lu, Weiwei Guo, Rui Ren, Simo Wu, Junrui Zhang, Yunpeng Li.

  Hypoxia is a crucial factor with type diversity that plays an important role in stem cell transplantation. However, the effects of hypoxia on adipose-derived stem cells (ADSCs) are largely unclear in the autologous fat transplantation (AFT) model, which shows a special type of "acute-progressively resolving hypoxia." Here, an AFT model in nude mice and a hypoxic culture model for ADSCs were combined to explore the link between hypoxia-inducible factor-1 α subunit (HIF-1α) and mitophagy under hypoxic conditions. The results showed that the activity of ADSCs in the first 7 days after grafting was the key stage for volume retention, and the expression of HIF-1α, light chain 3 beta (LC3B), and Beclin1 in ADSCs increased during this period. We also found that hypoxia for longer than 48 h damaged the differentiation and mitochondrial respiration of ADSCs in vitro, but hypoxia signals also activate HIF-1α to initiate mitophagy and maintain the activities of ADSCs. Pre-enhancing mitophagy by rapamycin effectively improves mitochondrial respiration in ADSCs after grafting and ultimately improves AFT outcomes.

Keywords:  HIF-1α; adipose-derived stem cells; autologous fat transplantation; cell transplantation; hypoxia; mitophagy

DOI:  https://doi.org/10.1177/09636897231210750
PLoS One. 2023 ;18(11): e0294700

Regular exercise attenuates alcoholic myopathy in zebrafish by modulating mitochondrial homeostasis.

Wei Wen, Cheng Guo, Zhanglin Chen, Dong Yang, Danting Zhu, Quwen Jing, Lan Zheng, Chenchen Sun, Changfa Tang.

Alcoholic myopathy is caused by chronic consumption of alcohol (ethanol) and is characterized by weakness and atrophy of skeletal muscle. Regular exercise is one of the important ways to prevent or alleviate skeletal muscle myopathy. However, the beneficial effects and the exact mechanisms underlying regular exercise on alcohol myopathy remain unclear. In this study, a model of alcoholic myopathy was established using zebrafish soaked in 0.5% ethanol. Additionally, these zebrafish were intervened to swim for 8 weeks at an exercise intensity of 30% of the absolute critical swimming speed (Ucrit), aiming to explore the beneficial effects and underlying mechanisms of regular exercise on alcoholic myopathy. This study found that regular exercise inhibited protein degradation, improved locomotion ability, and increased muscle fiber cross-sectional area (CSA) in ethanol-treated zebrafish. In addition, regular exercise increases the functional activity of mitochondrial respiratory chain (MRC) complexes and upregulates the expression levels of MRC complexes. Regular exercise can also improve oxidative stress and mitochondrial dynamics in zebrafish skeletal muscle induced by ethanol. Additionally, regular exercise can activate mitochondrial biogenesis and inhibit mitochondrial unfolded protein response (UPRmt). Together, our results suggest regular exercise is an effective intervention strategy to improve mitochondrial homeostasis to attenuate alcoholic myopathy.

DOI: https://doi.org/10.1371/journal.pone.0294700