bims-mikwok 2024-10-13 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–10–13
thirty-six papers selected by
Gavin McStay, Liverpool John Moores University

Coordinating BNIP3/NIX-mediated mitophagy in space and time.
A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.
DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration.
Drp1 Promotes Macrophage M1 Polarization and Inflammatory Response in Autoimmune Myocarditis by Driving Mitochondrial Fission.
Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.
CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction.
Myosin A and F-Actin play a critical role in mitochondrial dynamics and inheritance in Toxoplasma gondii.
Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.
CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.
Drp1 acetylation mediated by CDK5-AMPK-GCN5L1 axis promotes cerebral ischemic injury via facilitating mitochondrial fission.
Accelerated mitochondrial dynamics promote spermatogonial differentiation.
Forsythoside A mitigates osteoarthritis and inhibits chondrocyte senescence by promoting mitophagy and suppressing NLRP3 inflammasome via the Nrf2 pathway.
Decreased ATF5 level contributes to improved mitochondrial function in oocytes exposed to vitrification stress.
A Siah3 of relief: A role for mitophagy as a fail-safe during developmental axon pruning.
SGLT1 inhibition alleviates radiation-induced intestinal damage through promoting mitochondrial homeostasis.
FUNDC1-mediated mitophagy regulates photodamage independently of the PINK1/Parkin-dependent pathway.
Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats.
BL-918 Alleviates Early Brain Injury in Rats After Subarachnoid Hemorrhage by Reducing Oxidative Stress and Promoting Mitophagy Through the ULK1/PINK1/Parkin Pathway.
Graphene Oxide Quantum Dots-Preactivated Dental Pulp Stem Cells/GelMA Facilitates Mitophagy-Regulated Bone Regeneration.
Synaptic Mitochondria: a crucial factor in the aged hippocampus.
Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.
Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.
Inhibition of the FOXO1-ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control.
High-intensity exercise alongside insulin alleviates muscle atrophy in type 1 diabetes mellitus concomitant with modulation of mitophagy-related proteins in skeletal muscle.
53BP1 regulates the self-renewal ability of neural stem/progenitor cells through modulating mitochondrial homeostasis.
Flaviviruses manipulate mitochondrial processes to evade the innate immune response.
A dual-functional photosensitizer for mitochondria-targeting photodynamic therapy and synchronous polarity monitoring.
Gastric Cancer Actively Remodels Mechanical Microenvironment to Promote Chemotherapy Resistance via MSCs-Mediated Mitochondrial Transfer.
Effect of phosphatase and tensin homolog-induced putative kinase 1/ E3 ubiquitin ligase Parkin mediated mitochondrial autophagy on chronic kidney disease myocardial injury and the intervention mechanism of Shenshuai recipe.
NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR.
Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool.
The involvement of HDAC3 in the pathogenesis of lung injury and pulmonary fibrosis.
Unveiling the Power of Mitochondrial Fission and Fusion: A Five-Gene Signature for Personalized Prognosis in Gastric Cancer.
Mechanism of phospho-Ubls' specificity and conformational changes that regulate Parkin activity.

Biochem Soc Trans. 2024 Oct 08. pii: BST20221364. [Epub ahead of print]

Coordinating BNIP3/NIX-mediated mitophagy in space and time.

Natalie M Niemi, Jonathan R Friedman.

  Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.

Keywords:  autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.1042/BST20221364
Nat Commun. 2024 Oct 08. 15(1): 8723

A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.

Liankui Zhou, Liu Jiang, Lan Li, Chengchuan Ma, Peixue Xia, Wanqiu Ding, Ying Liu.

The abilities of an organism to cope with extrinsic stresses and activate cellular stress responses decline during aging. The signals that modulate stress responses in aged animals remain to be elucidated. Here, we discover that feeding Caenorhabditis elegans (C. elegans) embryo lysates to adult worms enabled the animals to activate the mitochondrial unfolded protein response (UPRmt) upon mitochondrial perturbations. This discovery led to subsequent investigations that unveil a hedgehog-like signal that is transmitted from the germline to the soma in adults to inhibit UPRmt in somatic tissues. Additionally, we find that the levels of germline-expressed piRNAs in adult animals markedly decreased. This reduction in piRNA levels coincides with the production and secretion of a hedgehog-like signal and suppression of the UPRmt in somatic cells. Building upon existing research, our study further elucidates the intricate mechanisms of germline-to-soma signaling and its role in modulating the trade-offs between reproduction and somatic maintenance within the context of organismal aging.

DOI: https://doi.org/10.1038/s41467-024-53064-0
EMBO J. 2024 Oct 08.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

  Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Keywords:  Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00242-x
Sci Signal. 2024 10 08. 17(857): eadn5805

Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration.

Omer Abraham, Shifra Ben-Dor, Inna Goliand, Rebecca Haffner-Krausz, Sarah Phoebeluc Colaiuta, Andrew Kovalenko, Avraham Yaron.

Mitophagy eliminates dysfunctional mitochondria, and defects in this cellular housekeeping mechanism are implicated in various age-related diseases. Here, we found that mitophagy suppression by the protein Siah3 promoted developmental axonal remodeling in mice. Siah3-deficient mice displayed increased peripheral sensory innervation. Cultured Siah3-deficient sensory neurons exhibited delays in both axonal degeneration and caspase-3 activation in response to withdrawal of nerve growth factor. Mechanistically, Siah3 was transcriptionally induced by the loss of trophic support and formed a complex with the cytosolic E3 ubiquitin ligase parkin, a core component of mitophagy, in transfected cells. Axons of Siah3-deficient neurons mounted profound mitophagy upon initiation of degeneration but not under basal conditions. Neurons lacking both Siah3 and parkin did not exhibit the delay in trophic deprivation-induced axonal degeneration or the induction of axonal mitophagy that was seen in Siah3-deficient neurons. Our findings reveal that mitophagy regulation acts as a gatekeeper of a physiological axon elimination program.

DOI: https://doi.org/10.1126/scisignal.adn5805
J Cardiovasc Transl Res. 2024 Oct 10.

Drp1 Promotes Macrophage M1 Polarization and Inflammatory Response in Autoimmune Myocarditis by Driving Mitochondrial Fission.

Lin Lin, Jin Wei, Jiahong Xue, Gang Fan, Wenjing Zhu, Yanhe Zhu, Ruiyun Wu.

  Autoimmune myocarditis (AM) is characterized by an intricate inflammatory response within the myocardium. Dynamin-related protein 1 (Drp1), a pivotal modulator of mitochondrial fission, plays a role in the pathogenesis of various diseases. A myosin-induced experimental autoimmune myocarditis (EAM) mouse model was successfully established. Flow cytometry was employed to detect M1/M2-like macrophages. Mitochondrial fragmentation was assessed using Mito-Tracker Red CMXRos. Drp1 was upregulated and activated in EAM mice. Depletion of Drp1 was observed to mitigate inflammation, macrophage infiltration and M1 polarization within the cardiac tissue of EAM mice. In M1-like macrophages derived from the hearts of EAM mice, Drp1 was found to promote mitochondrial fission and diminish mitochondrial fusion. Furthermore, the depletion of Drp1 reduced the NF-κB-related pro-inflammatory response in EAM-associated M1-like macrophages. Drp1 drives mitochondrial fission in macrophages, driving their M1 polarization and the subsequent inflammatory response. Drp1 may represent an effective target for the prevention and treatment of AM.

Keywords:  Autoimmune myocardioptis; Drp1; EAM mouse model; M1 polarization; Mitochondrial fission

DOI:  https://doi.org/10.1007/s12265-024-10570-2
Cell Commun Signal. 2024 Oct 10. 22(1): 485

Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.

Eunice Eun-Seo Chang, Huifang Liu, Zoe Yuen-Kiu Choi, Yasine Malki, Steffi Xi-Yue Zhang, Shirley Yin-Yu Pang, Michelle Hiu-Wai Kung, David B Ramsden, Shu-Leong Ho, Philip Wing-Lok Ho.

   BACKGROUND: Stress-induced activation of ERK/Drp1 serves as a checkpoint in the segregation of damaged mitochondria for autophagic clearance (mitophagy). Elevated cytosolic calcium (Ca2+) activates ERK, which is pivotal to mitophagy initiation. This process is altered in Parkinson's disease (PD) with mutations in leucine-rich repeat kinase 2 (LRRK2), potentially contributing to mitochondrial dysfunction. Pathogenic LRRK2 mutation is linked to dysregulated cellular Ca2+ signaling but the mechanism involved remains unclear.
METHODS: Mitochondrial damages lead to membrane depolarization. To investigate how LRRK2 mutation impairs cellular response to mitochondrial damages, mitochondrial depolarization was induced by artificial uncoupler (FCCP) in wild-type (WT) and LRRK2R1441G mutant knockin (KI) mouse embryonic fibroblasts (MEFs). The resultant cytosolic Ca2+ flux was assessed using live-cell Ca2+ imaging. The role of mitochondria in FCCP-induced cytosolic Ca2+ surge was confirmed by co-treatment with the mitochondrial sodium-calcium exchanger (NCLX) inhibitor. Cellular mitochondrial quality and function were evaluated by Seahorse™ real-time cell metabolic analysis, flow cytometry, and confocal imaging. Mitochondrial morphology was visualized using transmission electron microscopy (TEM). Activation (phosphorylation) of stress response pathways were assessed by immunoblotting.
RESULTS: Acute mitochondrial depolarization induced by FCCP resulted in an immediate cytosolic Ca2+ surge in WT MEFs, mediated predominantly via mitochondrial NCLX. However, such cytosolic Ca2+ response was abolished in LRRK2 KI MEFs. This loss of response in KI was associated with impaired activation of Ca2+/calmodulin-dependent kinase II (CaMKII) and MEK, the two upstream kinases of ERK. Treatment of LRRK2 inhibitor did not rescue this phenotype indicating that it was not caused by mutant LRRK2 kinase hyperactivity. KI MEFs exhibited swollen mitochondria with distorted cristae, depolarized mitochondrial membrane potential, and reduced mitochondrial Ca2+ store and mitochondrial calcium uniporter (MCU) expression. These mutant cells also exhibited lower cellular ATP: ADP ratio albeit higher basal respiration than WT, indicating compensation for mitochondrial dysfunction. These defects may hinder cellular stress response and signals to Drp1-mediated mitophagy, as evident by impaired mitochondrial clearance in the mutant.
CONCLUSIONS: Pathogenic LRRK2R1441G mutation abolished mitochondrial depolarization-induced Ca2+ response and impaired the basal mitochondrial clearance. Inherent defects from LRRK2 mutation have weakened the cellular ability to scavenge damaged mitochondria, which may further aggravate mitochondrial dysfunction and neurodegeneration in PD.

Keywords:  Calcium-dependent pathways; Cellular stress response; LRRK2 mutation; Mitochondrial dysfunction; Mitophagy; NCLX; Parkinson disease

DOI:  https://doi.org/10.1186/s12964-024-01844-y
Free Radic Biol Med. 2024 Oct 05. pii: S0891-5849(24)00960-2. [Epub ahead of print]225 181-192

CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction.

Ji Hyun Lee, Kyu Hwa Seo, Ji Hye Yang, Sam Seok Cho, Na Yeon Kim, Ji Hye Kim, Kyu Min Kim, Sung Hwan Ki.

  Hepatic stellate cells (HSCs) are primary cells for development and progression of liver fibrosis. Mitophagy is an essential lysosomal process for mitochondrial homeostasis, which can be activated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a representative mitochondrial uncoupler. However, little information is available on the role of CCCP-mediated mitophagy in HSC activation and liver fibrogenesis. In this study, we showed that CCCP treatment in HSCs caused mitochondrial dysfunction proved by decreased mitochondrial membrane potential, mitochondrial DNA, and ATP contents and increased mitochondrial ROS. Moreover, CCCP induced mitophagy and impaired mitophagy flux at the later stage. This blockade of mitophagic flux effect was mediated by suppression of lysosomal activity; CCCP decreased expression of lysosomal markers and cathepsin B activity, and increased lysosomal pH. Intriguingly, CCCP treatment in LX-2 cells or primary HSCs elevated plasminogen activator inhibitor-1 (PAI-1), a typical fibrogenic marker of HSCs which was attenuated by mitochondrial division inhibitor 1, a mitophagy inhibitor. The up-regulation of PAI-1 by CCCP was not due to altered transcriptional activity but lysosomal dysfunction. In vivo acute or sub-chronic treatment of CCCP to mice induced mitophagy and fibrogenesis of liver. Hepatic fibrogenic marker (PAI-1) was incremented with mitophagy markers (parkin and PTEN-induced putative kinase 1) in the livers of CCCP injected mice. Furthermore, we found that 5-aminoimidazole-4-carboxyamide ribonucleoside reversed CCCP-mediated mitophagy and subsequent HSC activation. To conclude, CCCP facilitated HSC activation and hepatic fibrogenesis via mitochondrial dysfunction and lysosomal blockade, implying that attenuation of CCCP-related signaling molecules may contribute to treat liver fibrosis.

Keywords:  AICAR; CCCP; Hepatic stellate cell; Liver fibrosis; Lysosome

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.259
PLoS Pathog. 2024 Oct 07. 20(10): e1012127

Myosin A and F-Actin play a critical role in mitochondrial dynamics and inheritance in Toxoplasma gondii.

Rodolpho Ornitz Oliveira Souza, Chunlin Yang, Gustavo Arrizabalaga.

The single mitochondrion of the obligate intracellular parasite Toxoplasma gondii is highly dynamic. Toxoplasma's mitochondrion changes morphology as the parasite moves from the intracellular to the extracellular environment and during division. Toxoplasma's mitochondrial dynamic is dependent on an outer mitochondrion membrane-associated protein LMF1 and its interaction with IMC10, a protein localized at the inner membrane complex (IMC). In the absence of either LMF1 or IMC10, parasites have defective mitochondrial morphology and inheritance defects. As little is known about mitochondrial inheritance in Toxoplasma, we have used the LMF1/IMC10 tethering complex as an entry point to dissect the machinery behind this process. Using a yeast two-hybrid screen, we previously identified Myosin A (MyoA) as a putative interactor of LMF1. Although MyoA is known to be located at the parasite's pellicle, we now show through ultrastructure expansion microscopy (U-ExM) that this protein accumulates around the mitochondrion in the late stages of parasite division. Parasites lacking MyoA show defective mitochondrial morphology and a delay in mitochondrion delivery to the daughter parasite buds during division, indicating that this protein is involved in organellar inheritance. Disruption of the parasite's actin network also affects mitochondrion morphology. We also show that parasite-extracted mitochondrion vesicles interact with actin filaments. Interestingly, mitochondrion vesicles extracted out of parasites lacking LMF1 pulled down less actin, showing that LMF1 might be important for mitochondrion and actin interaction. Accordingly, we are showing for the first time that actin and Myosin A are important for Toxoplasma mitochondrial morphology and inheritance.

DOI: https://doi.org/10.1371/journal.ppat.1012127
Commun Biol. 2024 Oct 05. 7(1): 1267

Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.

Wen-Wei Tseng, Ching-Hsiang Chu, Yi-Ju Lee, Shirui Zhao, Chen Chang, Yi-Ping Ho, An-Chi Wei.

Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges.

DOI: https://doi.org/10.1038/s42003-024-06955-3
Biochem Biophys Res Commun. 2024 Oct 05. pii: S0006-291X(24)01273-7. [Epub ahead of print]734 150737

CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.

Ruobing Li, Ti Qin, Yabo Guo, Shan Zhang, Xiaogang Guo.

  Microproteins synthesized through non-canonical translation pathways are frequently found within mitochondria. However, the functional significance of these mitochondria-localized microproteins in energy-intensive organs such as the heart remains largely unexplored. In this study, we demonstrate that the long non-coding RNA CD63-AS1 encodes a mitochondrial microprotein. Notably, in ribosome profiling data of human hearts, there is a positive correlation between the expression of CD63-AS1 and genes associated with cardiomyopathy. We have termed this microprotein CEAM (CD63-AS1 encoded amyloid-like motif containing microprotein), reflecting its sequence characteristics. Our biochemical assays show that CEAM forms protease-resistant aggregates within mitochondria, whereas deletion of the amyloid-like motif transforms CEAM into a soluble cytosolic protein. Overexpression of CEAM triggers mitochondrial stress responses and adversely affect mitochondrial bioenergetics in cultured cardiomyocytes. In turn, the expression of CEAM is reciprocally inhibited by the activation of mitochondrial stresses induced by oligomycin. When expressed in mouse hearts via adeno-associated virus, CEAM impairs cardiac function. However, under conditions of pressure overload-induced cardiac hypertrophy, CEAM expression appears to offer a protective benefit and mitigates the expression of genes associated with cardiac remodeling, presumably through a mechanism that suppresses stress-induced translation reprogramming. Collectively, our study uncovers a hitherto unexplored amyloid-like microprotein expressed in the human cardiomyocytes, offering novel insights into myocardial hypertrophy pathophysiology.

Keywords:  CD63-AS1; Microprotein; Mitochondrial unfolded protein response; Pressure overload-induced cardiac hypertrophy; Transverse aortic constriction

DOI:  https://doi.org/10.1016/j.bbrc.2024.150737
Mol Med. 2024 Oct 10. 30(1): 173

Drp1 acetylation mediated by CDK5-AMPK-GCN5L1 axis promotes cerebral ischemic injury via facilitating mitochondrial fission.

Jiejie Zhang, Shan Wang, Haitao Zhang, Xiaotong Yang, Xin Ren, Lei Wang, Yihan Yang, Yi Yang, Ya Wen.

  The aberrant acetylation of mitochondrial proteins is involved in the pathogenesis of multiple diseases including neurodegenerative diseases and cerebral ischemic injury. Previous studies have shown that depletion of mitochondrial NAD+, which is necessary for mitochondrial deacetylase activity, leads to decreased activity of mitochondrial deacetylase and thus causes hyperacetylation of mitochondrial proteins in ischemic brain tissues, which results in altered mitochondrial dynamics. However, it remains largely unknown about how mitochondrial dynamics-related protein Drp1 is acetylated in ischemic neuronal cells and brain tissues. Here, we showed that Drp1 and GCN5L1 expression was up-regulated in OGD-treated neuronal cells and ischemic brain tissues induced by dMCAO, accompanied by the increased mitochondrial fission, mtROS accumulation, and cell apoptosis. Further, we confirmed that ischemia/hypoxia promoted Drp1 interaction with GCN5L1 in neuronal cells and brain tissues. GCN5L1 knockdown attenuated, while its overexpression enhanced Drp1 acetylation and mitochondrial fission, indicating that GCN5L1 plays a crucial role in ischemia/hypoxia-induced mitochondrial fission by acetylating Drp1. Mechanistically, ischemia/hypoxia induced Drp1 phosphorylation by CDK5 upregulation-mediated activation of AMPK in neuronal cells, which in turn facilitated the interaction of GCN5L1 with Drp1, thus enhancing Drp1 acetylation and mitochondrial fission. Accordingly, inhibition of AMPK alleviated ischemia/hypoxia- induced Drp1 acetylation and mitochondrial fission and protected brain tissues from ischemic damage. These findings provide a novel insight into the functional roles of GCN5L1 in regulating Drp1 acetylation and identify a previously unrecognized CDK5-AMPK-GCN5L1 pathway that mediates the acetylation of Drp1 in ischemic brain tissues.

Keywords:  AMPK; Acetylation; CDK5; Drp1; GCN5L1; Ischemic stroke; Mitochondrial fission; Neuronal cells

DOI:  https://doi.org/10.1186/s10020-024-00948-y
Stem Cell Reports. 2024 Sep 28. pii: S2213-6711(24)00268-6. [Epub ahead of print]

Accelerated mitochondrial dynamics promote spermatogonial differentiation.

Zhaoran Zhang, Junru Miao, Hanben Wang, Izza Ali, Duong Nguyen, Wei Chen, Yuan Wang.

  At different stages of spermatogenesis, germ cell mitochondria differ remarkably in morphology, architecture, and functions. However, it remains elusive how mitochondria change their features during spermatogonial differentiation, which in turn impacts spermatogonial stem cell fate decision. In this study, we observed that mitochondrial fusion and fission were both upregulated during spermatogonial differentiation. As a result, the mitochondrial morphology remained unaltered. Enhanced mitochondrial fusion and fission promoted spermatogonial differentiation, while the deficiency in DRP1-mediated fission led to a stage-specific blockage of spermatogenesis at differentiating spermatogonia. Our data further revealed that increased expression of pro-fusion factor MFN1 upregulated mitochondrial metabolism, whereas DRP1 specifically regulated mitochondrial permeability transition pore opening in differentiating spermatogonia. Taken together, our findings unveil how proper spermatogonial differentiation is precisely controlled by concurrently accelerated and properly balanced mitochondrial fusion and fission in a germ cell stage-specific manner, thereby providing critical insights about mitochondrial contribution to stem cell fate decision.

Keywords:  DRP1; MFN1; mitochondrial dynamics; spermatogonial differentiation; spermatogonial stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2024.09.006
Phytomedicine. 2024 Oct 02. pii: S0944-7113(24)00709-8. [Epub ahead of print]135 156052

Forsythoside A mitigates osteoarthritis and inhibits chondrocyte senescence by promoting mitophagy and suppressing NLRP3 inflammasome via the Nrf2 pathway.

Wei Li, Yanlin Zhong, Zhencan Lin, Zengfa Deng, Dianbo Long, Ming Li, Changzhao Li, Guping Mao, Yan Kang.

   BACKGROUND: Chondrocyte senescence and inflammation are hallmarks of osteoarthritis (OA). Forsythiaside A (FTA), a phenylethanol glycoside isolated from air-dried fruits of Forsythia, has been reported to have significant anti-inflammatory and antioxidant properties. However, its protective effects against OA have not been elucidated.
PURPOSE: We explored the therapeutic efficacy of FTA in inhibiting chondrocyte senescence and inflammation during OA, as well as the potential underlying mechanisms.
STUDY DESIGN: This study aimed to investigate the novel mechanism of FTA in alleviating OA in both cell and animal models.
METHODS: The protective effect of FTA against tert‑butyl hydroperoxide-induced chondrocyte damage was assessed, and the effects of FTA on cartilage aging and OA progression were evaluated using a medial meniscus (DMM)-induced knee OA mouse model. The regulatory effects of FTA on the NLRP3 Inflammasome, mitophagy, and the PKC/Nrf2 pathway were also explored.
RESULTS: In vitro, FTA improved mitochondrial function, enhanced mitophagy, suppressed NLRP3 inflammasome activation, and inhibited chondrocyte senescence; however, these chondroprotective effects were partially reversed after mitophagy inhibition, NLRP3 inflammasome activation, and Nrf2 pathway inhibition. Furthermore, we found that FTA directly interacts with Nrf2 and enhances its phosphorylation by protein kinase C (PKC). In vivo, FTA attenuated the pathological signs of knee OA in a DMM-model mouse model, which was partially reversed by ML385.
CONCLUSION: FTA inhibited chondrocyte senescence and OA progression by activating the PKC-Nrf2 pathway. Thus, FTA is a potential novel therapeutic agent for OA.

Keywords:  Forsythiaside A; Nrf2; inflammasome; mitophagy; osteoarthritis; senescence

DOI:  https://doi.org/10.1016/j.phymed.2024.156052
Front Cell Dev Biol. 2024 ;12 1431683

Decreased ATF5 level contributes to improved mitochondrial function in oocytes exposed to vitrification stress.

Guizhen Zhou, Aiju Liu, Jiachen Bai, Hongyu Liu, Yixiao Zhu, Yuwen Luo, Lv Zheng, Yunpeng Hou, Jun Li, Xiangwei Fu.

   Background: Mitochondrial unfolded protein response (mtUPR) plays an essential role in the response of mitochondria to stress-induced damage. Activating of transcription factor 5 (ATF5) can help to sustain mitochondrial function and regulate organelle recovery under mitochondrial stress. Vitrification is a stressor that disrupts mitochondrial activity and cell homeostasis. However, little is known about the function of ATF5 in response to the extreme biophysical and chemical stresses during oocyte vitrification.
Methods: The expression of ATF5 and mtUPR biomarkers were measured in fresh and vitrified oocytes. Subsequently, oocytes with ATF5 deficiency were constructed by siRNA microinjection, and the function of ATF5 in mitochondrial function and oocyte development were analyzed in vitrified oocytes. Furthermore, transcriptome analysis was performed to uncover the molecular network regulated by ATF5 in response to oocyte vitrification.
Results: In the present study, the mitochondrial membrane potential and ATP levels were decreased in ATF5 knockdown oocytes, in line with the phenotypes observed in vitrified oocytes. In addition, ATF5 knockdown resulted in decreased mitochondrial temperature, reduced unfolded protein levels, abnormal mitochondrial dynamics (fusion and fission), and increased autophagy. Subsequent experiments indicated that mtUPR was suppressed in oocytes with ATF5 knockdown. Interestingly, ATF5 was aberrantly upregulated in oocytes exposed to vitrification stress. Reduced ATF5 expression to a homeostatic level in vitrified oocytes led to accumulated unfolded protein levels and increased mitochondrial membrane potential. Moreover, increased mitochondrial dynamics and an increased germinal vesicle breakdown (GVBD) rate were detected after in vitro maturation. Transcriptome analysis revealed that ATF5 is involved in the vitrification stress response, and ATF5 regulated the in vitro maturation potential in vitrified oocytes through the cAMP-PKA and PI3K/AKT pathways.
Discussion: Our findings indicate that mtUPR was initiated in response to vitrification stimuli, and downregulated ATF5 level to a homeostatic state contributes to improved mitochondrial function in oocytes exposed to vitrification stress. Our results highlight the crucial role of ATF5 in the regulation of mitochondrial function in vitrified oocytes through mediating mtUPR.

Keywords:  ATF5; mitochondrial dysfunction; mitochondrial unfolded protein responses; oocytes; vitrification

DOI:  https://doi.org/10.3389/fcell.2024.1431683
Sci Signal. 2024 10 08. 17(857): eads1228

A Siah3 of relief: A role for mitophagy as a fail-safe during developmental axon pruning.

Rina L Davidson, David J Simon.

Developmental axon pruning is controlled by a careful balance of pro- and anti-apoptotic signals, which are activated in response to external cues to sculpt mature neuronal circuitry. In this issue of Science Signaling, Abraham et al. define a safeguard against apoptotic axon pruning and illustrate that Siah3 represses Parkin-mediated mitophagy to control the availability of axonal mitochondria that activate the pruning process.

DOI: https://doi.org/10.1126/scisignal.ads1228
Free Radic Biol Med. 2024 Oct 09. pii: S0891-5849(24)00975-4. [Epub ahead of print]

SGLT1 inhibition alleviates radiation-induced intestinal damage through promoting mitochondrial homeostasis.

Wenlin Jiao, Yunyun Cheng, Chang Liu, Jie Feng, Jiguo Lin, Yannan Shen.

  Radiation-induced intestinal injury (RIII) constitutes a challenge in radiotherapy. Ionizing radiation (IR) induces DNA and mitochondrial damage by increasing reactive oxygen species (ROS). Sodium-glucose cotransporter 1 (SGLT1) is abundant in the gastrointestinal tract and the protective effects of inhibited SGLT1 in kidney and cardiovascular disease have been widely reported. However, the function of SGLT1 in RIII remains unclear. Herein, we reported that IR induced intestinal epithelial cell damage along with upregulation of SGLT1 in vivo and in vitro, which was alleviated by inhibition of SGLT1. Specifically, maintaining intestinal cell homeostasis was detected through cellular proliferation, apoptosis, and DNA damage assays, promoting epithelial regeneration and lifespan extension. Considering the importance of mitochondrial function in cell fate, we next confirmed that SGLT inhibition maintains mitochondrial homeostasis through enhanced mitophagy in intestinal epithelial cells. Finally, based on the bioinformatics analysis and cell validation, we demonstrated that inhibition of SGLT1 suppresses the PI3K/AKT/mTOR pathway to enhance mitophagy activation post-irradiation. In addition, we preliminarily demonstrate that SGLT inhibitors do not affect the radiosensitivity of tumors. Hence, our findings suggest that inhibition of SGLT is a promising therapeutic strategy to protect against RIII. To the best of our knowledge, this is the first report on the potential effect of SGLT1 inhibition in RIII.

Keywords:  Sodium-glucose cotransporters; mitophagy; radiation-induced intestinal injury

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.274
Free Radic Biol Med. 2024 Oct 08. pii: S0891-5849(24)00973-0. [Epub ahead of print]

FUNDC1-mediated mitophagy regulates photodamage independently of the PINK1/Parkin-dependent pathway.

Hailun He, Wenyue Huang, Lidan Xiong, Cong Ma, Yichong Wang, Peihong Sun, Dongxin Shi, Liangman Li, Hongwei Yan, Yan Wu.

   BACKGROUND: Ultraviolet B(UVB) triggers a pro-survival response through mitophagy, but the role of FUNDC1-mediated mitophagy in photodamaged skin remains unexplored.
OBJECTIVES: To clarify the function of mitophagy in UVB-induced photodamaged skin.
METHODS: To investigate the role of FUNDC1-mediated mitophagy in UVB-induced mitochondrial damage and cell apoptosis, FUNDC1 knockdown in C57BL/6 mice was performed using adeno-associated virus. Additionally, FUNDC1 overexpression and knockdown in HaCaT cells were conducted using lentivirus. A comprehensive analysis was conducted on a panel of human sun-exposed skin samples, alongside control samples, to assess the expression levels of FUNDC1.
RESULTS: In UVB-induced C57BL/6 mice, the dorsal skin showed photodamage including erythema, scaling, erosion, and scabs. The expression levels of PINK1, Parkin, and BNIP3 did not show significant changes, while FUNDC1 expression consistently declined along with LC3B. Cytochrome C, Bax, and cleaved-caspase3 were upregulated, while Bcl2 was downregulated. UVB-induced HaCaT cells showed mitochondrial damage, accompanied by FUNDC1 downregulation and BNIP3 upregulation, while PINK1 and Parkin showed no significant changes. FUNDC1 overexpression led to an increase in mtROS and a decrease in mitochondrial membrane potential and ATP levels, indicating complete mitochondrial clearance and exacerbated cell death. FUNDC1 knockdown protected against UVB-induced photodamage in mice and mitigated mitochondrial damage and apoptosis in HaCaT cells by activating compensatory PINK1/Parkin-dependent mitophagy, which was evidenced by upregulation of PINK1 and Bcl2 and downregulation of Bax. In human sun-exposed skin samples, there was a decrease in the number of FUNDC1+ cells compared with non-sun-exposed controls.
CONCLUSIONS: FUNDC1-mediated mitophagy regulates skin photodamage and provides a novel mechanism for resisting photodamage, presenting a potential target for future therapeutic interventions.

Keywords:  FUNDC1; UVB; mitochondrial apoptosis; mitophagy; photodamage

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.272
Sci Rep. 2024 Oct 11. 14(1): 23861

Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats.

Jane E Manganaro, Katy Emanuel, Benjamin G Lamberty, Joseph W George, Kelly L Stauch.

  Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk suggesting targeting the Pink1/Parkin pathway in the periphery might have therapeutic potential.

Keywords:  B cells; Energetics; Parkin; Pink1; Platelets; T cells

DOI:  https://doi.org/10.1038/s41598-024-74775-w
Free Radic Biol Med. 2024 Oct 03. pii: S0891-5849(24)00962-6. [Epub ahead of print]

BL-918 Alleviates Early Brain Injury in Rats After Subarachnoid Hemorrhage by Reducing Oxidative Stress and Promoting Mitophagy Through the ULK1/PINK1/Parkin Pathway.

Jinshuo Yang, Qiaowei Wu, Yuchen Li, Yongzhi Zhang, Shuai Lan, Kaikun Yuan, Jiaxing Dai, Bowen Sun, Yuxiao Meng, Shancai Xu, Huaizhang Shi.

   BACKGROUND AND PURPOSE: Oxidative stress plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The small molecule ULK1 agonist, BL-918, demonstrated neuroprotective effects in other central nervous system diseases; however, its role in SAH has not yet been explored. This study aimed to evaluate whether BL-918 could provide neuroprotective effects in rats following SAH.
METHODS: An SAH model was established in Sprague-Dawley rats using endovascular perforation. BL-918 was administered intraperitoneally after SAH, while the ULK1 inhibitor SBI was given intraperitoneally prior to SAH modeling. PINK1 siRNA was administered into the lateral ventricle before SAH induction. The neuroprotective effects and mechanisms of BL-918 were assessed through SAH grading, brain water content measurement, blood-brain barrier permeability, neurobehavioral tests, Western blot, immunofluorescence, TUNEL staining, DHE staining, and transmission electron microscopy (TEM).
RESULTS: After SAH, the expression levels of p-ULK1, PINK1, Parkin, and LC3Ⅱ increased, peaking at 24 hours post-SAH. BL-918 treatment improved neurological function in rats, reduced brain water content and blood-brain barrier permeability, and exhibited anti-oxidative stress and anti-apoptotic effects. Western blot analysis revealed that BL-918 increased the expression of p-ULK1, PINK1, Parkin, LC3Ⅱ, Bcl-xl, and Bcl-2 while inhibiting the expression of Bax and Cleaved Caspase-3. Oxidative stress-related indicators showed that BL-918 alleviated oxidative stress. Immunofluorescence and TEM results demonstrated that BL-918 promoted mitophagy and preserved mitochondrial morphology. Furthermore, the positive effects of BL-918 were reversed by SBI and PINK1 siRNA, respectively.
CONCLUSION: BL-918 promoted mitophagy through the ULK1/PINK1/Parkin signaling pathway, reduced oxidative stress following SAH, and improved both short-term and long-term neurological impairments. Thus, BL-918 treatment may offer a novel therapeutic approach for patients with SAH.

Keywords:  Early Brain Injury; Mitophagy; Oxidative stress; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.261
Int J Nanomedicine. 2024 ;19 10107-10128

Graphene Oxide Quantum Dots-Preactivated Dental Pulp Stem Cells/GelMA Facilitates Mitophagy-Regulated Bone Regeneration.

Xiaoyuan Yan, Na An, Zeying Zhang, Qiujing Qiu, Di Yang, Penggong Wei, Xiyue Zhang, Lihong Qiu, Jiajie Guo.

   Background: In bone tissue engineering (BTE), cell-laden scaffolds offer a promising strategy for repairing bone defects, particularly when host cell regeneration is insufficient due to age or disease. Exogenous stem cell-based BTE requires bioactive factors to activate these cells. Graphene oxide quantum dots (GOQDs), zero-dimensional derivatives of graphene oxide, have emerged as potential osteogenic nanomedicines. However, constructing biological scaffolds with GOQDs and elucidating their biological mechanisms remain critical challenges.
Methods: We utilized GOQDs with a particle size of 10 nm, characterized by a surface rich in C-O-H and C-O-C functional groups. We developed a gelatin methacryloyl (GelMA) hydrogel incorporated with GOQDs-treated dental pulp stem cells (DPSCs). These constructs were transplanted into rat calvarial bone defects to estimate the effectiveness of GOQDs-induced DPSCs in repairing bone defects while also investigating the molecular mechanism underlying GOQDs-induced osteogenesis in DPSCs.
Results: GOQDs at 5 μg/mL significantly enhanced the osteogenic differentiation of DPSCs without toxicity. The GOQDs-induced DPSCs showed active osteogenic potential in three-dimensional cell culture system. In vivo, transplantation of GOQDs-preactivated DPSCs/GelMA composite effectively facilitated calvarial bone regeneration. Mechanistically, GOQDs stimulated mitophagy flux through the phosphatase-and-tensin homolog-induced putative kinase 1 (PINK1)/Parkin E3 ubiquitin ligase (PRKN) pathway. Notably, inhibiting mitophagy with cyclosporin A prevented the osteogenic activity of GOQDs.
Conclusion: This research presents a well-designed bionic GOQDs/DPSCs/GelMA composite scaffold and demonstrated its ability to promote bone regeneration by enhancing mitophagy. These findings highlight the significant potential of this composite for application in BTE and underscore the crucial role of mitophagy in promoting the osteogenic differentiation of GOQDs-induced stem cells.

Keywords:  bone regeneration; dental pulp stem cells; graphene oxide quantum dots; mitophagy; osteogenesis

DOI:  https://doi.org/10.2147/IJN.S480979
Ageing Res Rev. 2024 Oct 04. pii: S1568-1637(24)00342-8. [Epub ahead of print] 102524

Synaptic Mitochondria: a crucial factor in the aged hippocampus.

Karina A Cicali, Cheril Tapia-Rojas.

  Aging is a multifaceted biological process characterized by progressive molecular and cellular damage accumulation. The brain hippocampus undergoes functional deterioration with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment. One of the factors contributing to this dysfunction is the loss of mitochondrial function. In neurons, mitochondria are categorized into synaptic and non-synaptic pools based on their location. Synaptic mitochondria, situated at the synapses, play a crucial role in maintaining neuronal function and synaptic plasticity, whereas non-synaptic mitochondria are distributed throughout other neuronal compartments, supporting overall cellular metabolism and energy supply. The proper function of synaptic mitochondria is essential for synaptic transmission as they provide the energy required and regulate calcium homeostasis at the communication sites between neurons. Maintaining the structure and functionality of synaptic mitochondria involves intricate processes, including mitochondrial dynamics such as fission, fusion, transport, and quality control mechanisms. These processes ensure that mitochondria remain functional, replace damaged organelles, and sustain cellular homeostasis at synapses. Notably, deficiencies in these mechanisms have been increasingly associated with aging and the onset of age-related neurodegenerative diseases. Synaptic mitochondria from the hippocampus are particularly vulnerable to age-related changes, including alterations in morphology and a decline in functionality, which significantly contribute to decreased synaptic activity during aging. This review comprehensively explores the critical roles that mitochondrial dynamics and quality control mechanisms play in preserving synaptic activity and neuronal function. It emphasizes the emerging evidence linking the deterioration of synaptic mitochondria to the aging process and the development of neurodegenerative diseases, highlighting the importance of these organelles from hippocampal neurons as potential therapeutic targets for mitigating cognitive decline and synaptic degeneration associated with aging. The novelty of this review lies in its focus on the unique vulnerability of hippocampal synaptic mitochondria to aging, underscoring their importance in maintaining brain function across the lifespan.

Keywords:  Aging; Cognitive Decline; Mitochondria; Mitochondrial Dysfunction; Non-synaptic; Synaptic

DOI:  https://doi.org/10.1016/j.arr.2024.102524
Ageing Res Rev. 2024 Oct 05. pii: S1568-1637(24)00340-4. [Epub ahead of print]101 102522

Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.

Roberto Iorio, Sabrina Petricca, Giovanna Di Emidio, Stefano Falone, Carla Tatone.

  Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.

Keywords:  Age-related diseases; Bioenergetic remodelling; Cancer; Intercellular communication; Mitochondria-specific ectocytosis; Mitochondrial derived vesicles (MDVs); Mitochondrial extracellular vesicles (mitoEVs); Mitochondrial quality control (MQC)

DOI:  https://doi.org/10.1016/j.arr.2024.102522
bioRxiv. 2024 Sep 24. pii: 2024.09.20.614121. [Epub ahead of print]

Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.

Hyejin Hwang, Brandon J Berry, Claudette St Croix, Andrew P Wojtovich, Sruti P Shiva, Arjumand Ghazi.

Reproductive status influences metabolism and health across lifespan in diverse ways and mitochondrial function playing a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.

DOI: https://doi.org/10.1101/2024.09.20.614121
Dev Cell. 2024 Oct 07. pii: S1534-5807(24)00532-X. [Epub ahead of print]59(19): 2549-2565

Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.

Jesminara Khatun, Jesse D Gelles, Jerry Edward Chipuk.

  The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life, and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondrial crosstalk with numerous regulated cell death (RCD) pathways controls the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery, as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die.

Keywords:  apoptosis; cell biology; cell death; ferroptosis; membranes; mitochondria; mitochondrial dynamics; signal transduction

DOI:  https://doi.org/10.1016/j.devcel.2024.09.004
Life Sci. 2024 Oct 05. pii: S0024-3205(24)00674-X. [Epub ahead of print]357 123084

Inhibition of the FOXO1-ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control.

Chunnian Ren, Linyun Xi, Hongbo Li, Zhengxia Pan, Yonggang Li, Gang Wang, Jiangtao Dai, Dawei He, Shulei Fan, Quan Wang.

   INTRODUCTION: Persistent chronic myocardial hypoxia causes disturbances in mitochondrial quality control (MQC), ultimately leading to increased cardiomyocyte injury in patients with Tetralogy of Fallot (TOF). The present study aimed to identify the key effector molecules of cardiomyocyte injury under chronic hypoxia in TOF.
METHODS: Clinical data from TOF patients were collected and whole transcriptome sequencing was performed on myocardial samples. Chronic hypoxia models were established in cardiac-specific knockout mice and cardiomyocytes, and a series of molecular experiments were used to determine the specific mechanisms involved.
RESULTS: Clinical cohort data and whole-transcriptome sequencing analysis of myocardial samples from TOF patients revealed that forkhead box O1 (FOXO1) plays an important role in chronic hypoxic cardiomyocyte injury. In a model of chronic hypoxia established in FOXO1 cardiac-specific knockout mice and FOXO1 gene-deficient cardiomyocytes, the AMPK signaling pathway regulates the expression of FOXO1, which in turn disrupts MQC by regulating the transcriptional activation of Rho-associated protein kinase 1 (ROCK1), and increasing the production of mitochondrial ROS, thereby exacerbating damage to cardiomyocytes. Excessive reactive oxygen species (ROS) production during MQC dysfunction further activates Cox7a2L to increase the assembly of the respiratory chain supercomplex. In addition, we found that miR-27b-3p partially binds to the 3' untranslated region of FOXO1 to exert a protective effect.
CONCLUSIONS: Maintenance of MQC under chronic hypoxia is achieved through a series of injury-protection mechanisms, suggesting that FOXO1 inhibition may be crucial for future mitigation of chronic hypoxic cardiomyocyte injury in TOF.

Keywords:  Chronic hypoxia; Cox7a2L; Forkhead box O1; Mitochondrial quality control; Tetralogy of Fallot

DOI:  https://doi.org/10.1016/j.lfs.2024.123084
Arch Physiol Biochem. 2024 Oct 09. 1-13

High-intensity exercise alongside insulin alleviates muscle atrophy in type 1 diabetes mellitus concomitant with modulation of mitophagy-related proteins in skeletal muscle.

Manal Moustafa Mahmoud, Nahed Qutb Abdel Hameed, Basant Adel Al Dreny Abd Al Latef, Samaa Samir Kamar, Laila Ahmed Rashed, Sarah Ali Abdelhameed Gouda.

  Background: Diabetes patients' quality of life can be severely impacted by diabetic muscle atrophy.Aim: This study aimed to explore the impact of high-intensity exercise (HIE) alongside insulin treatment on muscle atrophy in a rat model of type 1 diabetes mellitus (T1DM).Methodology: Fifty rats were allocated into five groups; Group 1, control sedentary (CS), T1DM was elicited in the rest of the groups by giving them Streptozotocin (STZ) (60 mg/kg), where group 2 (DS) remained sedentary, while groups 3,4,5 were treated with insulin after induction of diabetes. Group 4 (DI+MIE) and 5 (DI+ HIE) underwent moderate and high-intensity exercise, respectively.Results: HIE for 14 days combined with insulin treatment significantly restored muscle strength and mass with a significant modification in the mitophagy-related proteins and fibroblast growth factor 21 (FGF 21) compared to other treated groups.Conclusion: This study concluded that there is a therapeutic role for HIE with insulin against T1DM-induced muscle atrophy.

Keywords:  FGF 21; Type 1 DM; high-intensity exercise; mitophagy; muscle atrophy

DOI:  https://doi.org/10.1080/13813455.2024.2410791
Biochem Biophys Res Commun. 2024 Oct 02. pii: S0006-291X(24)01312-3. [Epub ahead of print]734 150776

53BP1 regulates the self-renewal ability of neural stem/progenitor cells through modulating mitochondrial homeostasis.

Yumi Sunatani, Ryo Sakasai, Tadashi Matsui, Kuniyoshi Iwabuchi.

  The regulation of intracellular reactive oxygen species (ROS) levels is important for maintaining the self-renewal ability of neural stem/progenitor cells (NSCs). In this study, we demonstrate that 53BP1, a DNA damage response factor known to facilitate the repair of DNA double-strand breaks, supports the maintenance of NSC stemness. ReNcell VM human NSCs with depleted 53BP1 exhibited reduced self-renewal ability compared with control NSCs, as revealed by a decrease in neurosphere size and an increase in differentiation into neural or glial cells within an NSC culture. Furthermore, 53BP1 depletion elevated cellular ROS levels, accompanied by mitochondrial abnormalities. The reduced self-renewal ability and elevated ROS levels in 53BP1-deficient NSCs were restored with the treatment of a radical scavenger, N-acetyl-l-cysteine. In addition, we investigated the functional relationship in the NSC self-renewal ability between 53BP1 and ataxia-telangiectasia mutated (ATM) or forkhead box O3a (FOXO3a), factors required for mitochondrial homeostasis, and the maintenance of NSC stemness. We found that ATM inhibition or FOXO3a deficiency, in addition to 53BP1 deficiency, did not induce further NSC stemness impairment. Collectively, our findings show that 53BP1, by cooperatively functioning with ATM and FOXO3a, supports the maintenance of NSC stemness by modulating mitochondrial homeostasis.

Keywords:  53BP1; Ataxia-telangiectasia mutated (ATM); Forkhead box O3a (FOXO3a); Neural stem cell; Reactive oxygen species (ROS); Stemness

DOI:  https://doi.org/10.1016/j.bbrc.2024.150776
Npj Viruses. 2024 ;2(1): 47

Flaviviruses manipulate mitochondrial processes to evade the innate immune response.

RuthMabel Boytz, Kadiatou Keita, Joanna B Pawlak, Maudry Laurent-Rolle.

  Mitochondria are essential eukaryotic organelles that regulate a range of cellular processes, from metabolism to calcium homeostasis and programmed cell death. They serve as essential platforms for antiviral signaling proteins during the innate immune response to viral infections. Mitochondria are dynamic structures, undergoing frequent fusion and fission processes that regulate various aspects of mitochondrial biology, including innate immunity. Pathogens have evolved sophisticated mechanisms to manipulate mitochondrial morphology and function to facilitate their replication. In this review, we examine the emerging literature on how flaviviruses modulate mitochondrial processes.

Keywords:  Immunology; Microbiology

DOI:  https://doi.org/10.1038/s44298-024-00057-x
J Mater Chem B. 2024 Oct 08.

A dual-functional photosensitizer for mitochondria-targeting photodynamic therapy and synchronous polarity monitoring.

Liu Yang, Shenglong Gan, Jie Zhang, Yin Jiang, Qingxin Chen, Hongyan Sun.

Mitochondria-targeting photodynamic therapy (PDT) has been validated as an effective strategy for inducing cell death through the disruption of mitochondrial function. The mitochondrial microenvironment, such as viscosity, polarity, pH and proteins, undergoes dynamic changes during PDT treatment, and investigating these parameters is crucial for comprehending the intrinsic mechanisms at the cellular level. In this context, disclosure of mitochondrial microenvironment alterations holds significant importance. Nevertheless, a probe capable of visualizing mitochondrial polarity fluctuations during PDT treatment has not been reported. Importantly, a dual-functional photosensitizer (PS) with polarity detection capability is highly advantageous as it can mitigate potential metabolic and localization disparities between the PS and the polarity probe, thus improving the accuracy of detection. In this contribution, a series of potential PSs were prepared by integrating the 2,1,3-benzoxadiazole (BD) scaffold with various heteroatom-incorporated electron-withdrawing groups. Among them, BDI exhibited potent phototoxicity against cancer cells and remarkable sensitivity to polarity changes, establishing it as a dual-functional PS for both photodynamic therapy and polarity detection. Leveraging its polarity detection capability, BDI successfully discriminated mitochondrial polarity discrepancy between cancer cells and normal cells, and indicated mitochondrial polarity fluctuations during drug-induced mitophagy. Crucially, BDI was employed to unveil mitochondrial polarity variations during PDT treatment, underscoring its dual function. Altogether, the meticulous design of the dual-functional PS BDI offers valuable insights into intracellular microenvironment variations during the PDT process, thereby enhancing our understanding and guiding the optimization of PDT treatment.

DOI: https://doi.org/10.1039/d4tb01872a
Adv Sci (Weinh). 2024 Oct 11. e2404994

Gastric Cancer Actively Remodels Mechanical Microenvironment to Promote Chemotherapy Resistance via MSCs-Mediated Mitochondrial Transfer.

Xin He, Li Zhong, Nan Wang, Baiwei Zhao, Yannan Wang, Xinxiang Wu, Changyu Zheng, Yueheng Ruan, Jianfeng Hou, Yusheng Luo, Yuehan Yin, Yulong He, Andy Peng Xiang, Jiancheng Wang.

  Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA-resistant GC patients and analyzed tumor tissues by single-cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis-independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), which could repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical-related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical-related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.

Keywords:  RhoA/ROCK1 signaling pathway; gastric cancer; matrix stiffness; oxaliplatin resistance

DOI:  https://doi.org/10.1002/advs.202404994
J Tradit Chin Med. 2024 Oct;44(5): 934-943

Effect of phosphatase and tensin homolog-induced putative kinase 1/ E3 ubiquitin ligase Parkin mediated mitochondrial autophagy on chronic kidney disease myocardial injury and the intervention mechanism of Shenshuai recipe.

Zhang Gedi, Liu Gengxin, Guo Min, Luo Fuli, Yan Ziyou, G E Wei.

   OBJECTIVE: To study whether Shenshuai recipe (, SSR) can play a protective role on chronic kidney disease myocardial injury model through phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/E3 ubiquitin ligase Parkin (Parkin) mitochondrial autophagy pathway.
METHODS: Forty-eight nephrectomized rats were randomly divided into six groups: sham-operated group, model group, Benazepril group, low, medium and high-dose groups of SSR. The rats were given the cor-responding intervention for six weeks, then were sacrificed. Serum was examined by enzyme linked immunosorbent assay (ELISA). Cardiac ultrasound was used to detect cardiac function in 5/6 nephrectomized rats. Myocardial tissue was examined by light and electron microscopy; PINK1, Parkin, microtubule-associated protein1 light chain 3 II (LC3B), sequestosome 1 (P62), BECN1 (Beclin-1) and dynamin-related protein 1 (Drp-1) were measured by real time polymerase chain reaction (RT-PCR), Western blot (WB) and immunohistochemistry (IHC).
RESULTS: The expression levels of blood urea nitrogen (BUN) and creatinine (SCr) in the model group were significantly higher than those in the sham-operated group, indicating that modeling was successful. SSR can protect myocardium by reducing the relative expression of creatine kinase myocardial isoenzyme and hypersensitivity cardiac troponin I (P<0.05). SSR can improve cardiac function in rats after ultrasound testing. SSR can improve the pathological manifestations of myocardial tissue after Masson staining. SSR can increase the number of autophagosomes and autophagiclysosomes in 5/6 nephrectomized rats (P<0.05). Determined by RT-PCR, WB and IHC, SSR can increase the relative expression of PINK1, Parkin, and LC3B (P<0.05), and decrease the relative expression of P62, Beclin-1 and Drp-1 (P<0.05).
CONCLUSIONS: The PINK1/Parkin mitochondrial autophagy pathway in myocardial tissues in 5/6 nephrectomy CKD myocardial injury rats was inhibited. SSR can activate PINK1/Parkin mitochondrial autophagy to enhance mitochondrial autophagy, and play a protective role in myocardial tissues.

Keywords:  PTEN phosphohydrolase; Shenshuai recipe; mitochondrial autophagy; myocardial injury; renal insufficiency, chronic; ubiquitin-protein ligases

DOI:  https://doi.org/10.19852/j.cnki.jtcm.20231231.001
Cell Death Dis. 2024 Oct 11. 15(10): 744

NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR.

Xi Xiong, Jialong Hou, Yi Zheng, Tao Jiang, Xuemiao Zhao, Jinlai Cai, Jiani Huang, Haijun He, Jiaxue Xu, Shuangjie Qian, Yao Lu, XinShi Wang, Wenwen Wang, Qianqian Ye, Shuoting Zhou, Mengjia Lian, Jian Xiao, Weihong Song, Chenglong Xie.

Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer's disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD+-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPRmt-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD+ metabolic profiles and improves MSR through the ATF4-dependent UPRmt pathway in AD-related cross-species models. At the organismal level, NAD+ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan.

DOI: https://doi.org/10.1038/s41419-024-07062-1
bioRxiv. 2024 Sep 23. pii: 2024.09.23.614531. [Epub ahead of print]

Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool.

Eleanor Meader, Morgan T Walcheck, Mindy R Leder, Ran Jing, Paul J Wrighton, Wade W Sugden, Mohamad A Najia, Isaac M Oderberg, Vivian M Taylor, Zachary C LeBlanc, Eleanor D Quenzer, Sung-Eun Lim, George Q Daley, Wolfram Goessling, Trista E North.

Embryonic hematopoietic stem and progenitor cells (HSPCs) have the unique ability to undergo rapid proliferation while maintaining multipotency, a clinically-valuable quality which currently cannot be replicated in vitro. Here, we show that embryonic HSPCs achieve this state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of Tg(ubi:mitoQC) zebrafish indicate that mitophagy initiates as HSPCs undergo endothelial-to-hematopoietic transition and colonize the caudal hematopoietic tissue (CHT). Knockdown of bnip3lb reduced mitophagy and HSPC numbers in the CHT by promoting myeloid-biased differentiation and apoptosis, which was rescued by anti-oxidant exposure. Conversely, induction of mitophagy enhanced both embryonic HSPC and lymphoid progenitor numbers. Significantly, mitophagy activation improved ex vivo functional capacity of hematopoietic progenitors derived from human-induced pluripotent stem cells (hiPSCs), enhancing serial-replating hematopoietic colony forming potential.
HIGHLIGHTS: ROS promotes HSPC formation in the dorsal aorta but negatively affects maintenance thereafter.HSPCs colonizing secondary niches control ROS levels via Bnip3lb-directed mitophagy.Mitophagy protects nascent HSPCs from ROS-associated apoptosis and maintains multipotency.Induction of mitophagy enhances long-term hematopoietic potential of iPSC-derived HSPCs.

DOI: https://doi.org/10.1101/2024.09.23.614531
Front Immunol. 2024 ;15 1392145

The involvement of HDAC3 in the pathogenesis of lung injury and pulmonary fibrosis.

Hanming Yu, Shi Liu, Shuo Wang, Xiu Gu.

  Acute lung injury (ALI) and its severe counterpart, acute respiratory distress syndrome (ARDS), are critical respiratory conditions with high mortality rates due primarily to acute and intense pulmonary inflammation. Despite significant research advances, effective pharmacological treatments for ALI and ARDS remain unavailable, highlighting an urgent need for therapeutic innovation. Notably, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the irreversible progression of fibrosis, which is initiated by repeated damage to the alveolar epithelium and leads to excessive extracellular matrix deposition. This condition is further complicated by dysregulated tissue repair and fibroblast dysfunction, exacerbating tissue remodeling processes and promoting progression to terminal pulmonary fibrosis. Similar to that noted for ALI and ARDS, treatment options for IPF are currently limited, with no specific drug therapy providing a cure. Histone deacetylase 3 (HDAC3), a notable member of the HDAC family with four splice variants (HD3α, -β, -γ, and -δ), plays multiple roles. HDAC3 regulates gene transcription through histone acetylation and adjusts nonhistone proteins posttranslationally, affecting certain mitochondrial and cytoplasmic proteins. Given its unique structure, HDAC3 impacts various physiological processes, such as inflammation, apoptosis, mitochondrial homeostasis, and macrophage polarization. This article explores the intricate role of HDAC3 in ALI/ARDS and IPF and evaluates its therapeutic potential the treatment of these severe pulmonary conditions.

Keywords:  acute lung injury; histone deacetylase 3; inflammation; macrophage; pulmonary fibrosis

DOI:  https://doi.org/10.3389/fimmu.2024.1392145
Curr Med Chem. 2024 Oct 08.

Unveiling the Power of Mitochondrial Fission and Fusion: A Five-Gene Signature for Personalized Prognosis in Gastric Cancer.

Bin Zhou, Ping Tie, Dongbing Li, You Lu, Yuanhua Liu.

   BACKGROUND: Mitochondrial fission and fusion play important roles in tumorigenesis, progression and therapy. Dysregulation of these processes may lead to tumor progression, and regulation of these processes may provide novel strategies for cancer therapy. The involvement of genes related to mitochondrial fission and fusion (MD) in gastric cancer (GC) remains poorly understood.
OBJECTIVE: The aim of this study was to establish an MD gene signature for GC patients and to investigate its association with prognosis, tumor microenvironment and treatment response in GC.
METHODS: We use the TCGA-GC database as the cohort, focusing specifically on genes associated with MD. We conducted identification and consistency clustering analysis of differentially expressed genes in MD, conducted MD gene mutation and copy number variation analysis, as well as correlation and functional enrichment analysis between MD gene cluster classification and immune infiltration. TCGA-GC and GSE15459 were used to construct training and validation cohorts for the model. We used various statistical methods, including Cox and Lasso regression, to develop the model. We validated the model using bulk transcriptome and single- cell transcriptome datasets (GSE13861, GSE26901, GSE66229, and GSE13450). We used GSEA enrichment, CIBERSORT algorithm, ESTIMATE, and TIDE to gain insight into the annotation of MD signature and the characterization of the tumor microenvironment. OncoPredict was used to analyze the relationship between the PRG signature and the drug sensitivity. We validated the expression of several key genes in MD signature on GC cell lines using quantitative real-time PCR (qRT-PCR).
RESULTS: These MDs-related subtypes exhibited different prognosis and immune filtration patterns. A five-gene signature, comprising AGT, HCFC1, KIFC3, NOX4, and RIN1, was developed. There was a clear distinction in overall survival between low- and high-risk patients. The analyses showed further confirmation of the independent prognostic value of the gene signature. There was a notable correlation between the MD signature, immune infiltration and drug susceptibility. The expression levels of AGT, HCFC1, KIFC3, NOX4 and RIN1 mRNA were all increased in these GC cells.
CONCLUSION: The MD signature has the capacity to significantly contribute to the prediction of personalized outcomes and the advancement of novel therapeutic strategies tailored for GC patients.

Keywords:  Gastric cancer; drug sensitivity; mitochondrial fission and fusion; prognosis; signature.; tumor microenvironment

DOI:  https://doi.org/10.2174/0109298673339515240930053412
Structure. 2024 Sep 26. pii: S0969-2126(24)00381-2. [Epub ahead of print]

Mechanism of phospho-Ubls' specificity and conformational changes that regulate Parkin activity.

Dipti Ranjan Lenka, Shradha Chaurasiya, Loknath Ratnakar, Atul Kumar.

  PINK1 and Parkin mutations lead to the early onset of Parkinson's disease. PINK1-mediated phosphorylation of ubiquitin (Ub), ubiquitin-like protein (NEDD8), and ubiquitin-like (Ubl) domain of Parkin activate autoinhibited Parkin E3 ligase. The mechanism of various phospho-Ubls' specificity and conformational changes leading to Parkin activation remain elusive. Herein, we show that compared to Ub, NEDD8 is a more robust binder and activator of Parkin. Structures and biophysical/biochemical data reveal specific recognition and underlying mechanisms of pUb/pNEDD8 and pUbl domain binding to the RING1 and RING0 domains, respectively. Also, pUb/pNEDD8 binding in the RING1 pocket promotes allosteric conformational changes in Parkin's catalytic domain (RING2), leading to Parkin activation. Furthermore, Parkinson's disease mutation K211N in the RING0 domain was believed to perturb Parkin activation due to loss of pUb binding. However, our data reveal allosteric conformational changes due to N211 that lock RING2 with RING0 to inhibit Parkin activity without disrupting pNEDD8/pUb binding.

Keywords:  NEDD8; PINK1; Parkin; Parkinson's disease; RBR E3 ligase; X-ray crystallography; ubiquitin

DOI:  https://doi.org/10.1016/j.str.2024.09.012