bims-mikwok 2023-12-24 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒12‒24
seventeen papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondrial quality control pathways sense mitochondrial protein import.
Mitochondrial quality control via organelle and protein degradation.
FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
Generation of inducible mitophagy mice.
The role of mitochondrial quality control in chronic obstructive pulmonary disease.
Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis.
Dynamin-related protein 1 is a critical regulator of mitochondrial calcium homeostasis during myocardial ischemia/reperfusion injury.
Gene dosage adaptations to mtDNA depletion and mitochondrial protein stress in budding yeast.
Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.
Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions.
Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
Melatonin protects against myocardial ischemia-reperfusion injury by inhibiting excessive mitophagy through the Apelin/SIRT3 signaling axis.
Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes.
Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis.
DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.

Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]

Mitochondrial quality control pathways sense mitochondrial protein import.

Laurie P Lee-Glover, Timothy E Shutt.

  Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.

Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy

DOI:  https://doi.org/10.1016/j.tem.2023.11.004
J Biochem. 2023 Dec 15. pii: mvad106. [Epub ahead of print]

Mitochondrial quality control via organelle and protein degradation.

Koji Yamano, Hiroki Kinefuchi, Waka Kojima.

  Mitochondria are essential eukaryotic organelles that produce ATP as well as synthesize various macromolecules. They also participate in signaling pathways such as the innate immune response and apoptosis. These diverse functions are performed by >1000 different mitochondrial proteins. Although mitochondria are continuously exposed to potentially damaging conditions such as reactive oxygen species, proteases/peptidases localized in different mitochondrial sub-compartments, termed mitoproteases, maintain mitochondrial quality and integrity. In addition to processing incoming precursors and degrading damaged proteins, mitoproteases also regulate metabolic reactions, mitochondrial protein half-lives, and gene transcription. Impaired mitoprotease function is associated with various pathologies. In this review, we highlight recent advances in our understanding of mitochondrial quality control regulated by autophagy, ubiquitin-proteasomes, and mitoproteases.

Keywords:  autophagy; mitophagy; peptidase; protease; ubiquitin

DOI:  https://doi.org/10.1093/jb/mvad106
Trends Mol Med. 2023 Dec 19. pii: S1471-4914(23)00279-4. [Epub ahead of print]

FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.

Kun Gao, Xiayun Xu, Chenji Wang.

  Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.

Keywords:  BNIP3/BNIP3L; FBXL4; MTDPS13; mitochondria; mitophagy; ubiquitination

DOI:  https://doi.org/10.1016/j.molmed.2023.11.017
Biomolecules. 2023 Dec 13. pii: 1789. [Epub ahead of print]13(12):

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Jose Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Mónica Álvarez-Córdoba, Manuel Munuera-Cabeza, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Antonio Sánchez-Alcázar.

  Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

Keywords:  ageing; mitochondria; mitochondrial biogenesis; mitochondrial diseases; mitochondrial dynamics; mitochondrial quality control mechanisms; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases; therapeutic target

DOI:  https://doi.org/10.3390/biom13121789
Genes Cells. 2023 Dec 22.

Generation of inducible mitophagy mice.

Toshiyuki Nishiji, Atsushi Hoshino, Yuki Uchio, Satoaki Matoba.

  Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR. To evaluate the activation of mitophagy upon doxycycline treatment, we also generated mitophagy reporter mito-QC mice in which mitochondria tandemly express mCherry and GFP, and only GFP signals are lost in acidic lysosomes subjected to mitophagy. With the ROSA26 promoter-driven rtTA, mitophagy was observed at least in heart, liver, and skeletal muscle. We investigated the relationship between mitophagy activation and pressure overload heart failure or high fat diet-induced obesity. Unexpectedly, we were unable to confirm the protective effect of mitophagy in these two pathological models. Further titration of the level of mitophagy induction is required to demonstrate the potency of the protective effects of mitophagy in disease models.

Keywords:  bioengineering; heart failure; mitophagy

DOI:  https://doi.org/10.1111/gtc.13091
Lab Invest. 2023 Dec 15. pii: S0023-6837(23)00250-7. [Epub ahead of print] 100307

The role of mitochondrial quality control in chronic obstructive pulmonary disease.

Yu-Biao Liu, Jie-Ru Hong, Nan Jiang, Ling Jin, Wen-Jing Zhong, Chen-Yu Zhang, Hui-Hui Yang, Jia-Xi Duan, Yong Zhou.

  Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and healthcare use worldwide with heterogeneous pathogenesis. Mitochondria, the powerhouses in cells responsible for oxidative phosphorylation and energy production, play essential roles in intracellular material metabolism, natural immunity, and cell death regulation. Therefore, it is crucial to address the urgent need for fine-tuning the regulation of mitochondrial quality to combat COPD effectively. Mitochondrial quality control (MQC) mainly refers to the selective removal of damaged or aging mitochondria and the generation of new mitochondria, which involves mitochondrial biogenesis, mitochondrial dynamics, mitophagy, etc. Mounting evidence suggests that mitochondrial dysfunction is a crucial contributor to the development and progression of COPD. This article mainly reviews the effects of MQC on COPD as well as their specific regulatory mechanisms. Finally, the therapeutic approaches of COPD via MQC are also illustrated.

Keywords:  chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1016/j.labinv.2023.100307
Cell Commun Signal. 2023 Dec 15. 21(1): 357

Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis.

Wenxin Tang, Chaoying Yan, Shuxuan He, Mengyu Du, Bo Cheng, Bin Deng, Shan Zhu, Yansong Li, Qiang Wang.

  BACKGROUND: Type 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood.METHODS: Here, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction.
RESULTS: As previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3β to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings.
CONCLUSIONS: Overall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD. Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3β and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis. Video Abstract.

Keywords:  Caveolin-1; Diabetes-associated cognitive dysfunction; Mitochondrial fission; Mitophagy

DOI:  https://doi.org/10.1186/s12964-023-01328-5
FASEB J. 2024 Jan;38(1): e23379

Dynamin-related protein 1 is a critical regulator of mitochondrial calcium homeostasis during myocardial ischemia/reperfusion injury.

Lin Piao, Yong-Hu Fang, Michael Fisher, Robert B Hamanaka, Alaa Ousta, Rongxu Wu, Gökhan M Mutlu, Alfredo J Garcia, Stephen L Archer, Willard W Sharp.

Dynamin-related protein 1 (Drp1) is a cytosolic GTPase protein that when activated translocates to the mitochondria, meditating mitochondrial fission and increasing reactive oxygen species (ROS) in cardiomyocytes. Drp1 has shown promise as a therapeutic target for reducing cardiac ischemia/reperfusion (IR) injury; however, the lack of specificity of some small molecule Drp1 inhibitors and the reliance on the use of Drp1 haploinsufficient hearts from older mice have left the role of Drp1 in IR in question. Here, we address these concerns using two approaches, using: (a) short-term (3 weeks), conditional, cardiomyocyte-specific, Drp1 knockout (KO) and (b) a novel, highly specific Drp1 GTPase inhibitor, Drpitor1a. Short-term Drp1 KO mice exhibited preserved exercise capacity and cardiac contractility, and their isolated cardiac mitochondria demonstrated increased mitochondrial complex 1 activity, respiratory coupling, and calcium retention capacity compared to controls. When exposed to IR injury in a Langendorff perfusion system, Drp1 KO hearts had preserved contractility, decreased reactive oxygen species (ROS), enhanced mitochondrial calcium capacity, and increased resistance to mitochondrial permeability transition pore (MPTP) opening. Pharmacological inhibition of Drp1 with Drpitor1a following ischemia, but before reperfusion, was as protective as Drp1 KO for cardiac function and mitochondrial calcium homeostasis. In contrast to the benefits of short-term Drp1 inhibition, prolonged Drp1 ablation (6 weeks) resulted in cardiomyopathy. Drp1 KO hearts were also associated with decreased ryanodine receptor 2 (RyR2) protein expression and pharmacological inhibition of the RyR2 receptor decreased ROS in post-IR hearts suggesting that changes in RyR2 may have a role in Drp1 KO mediated cardioprotection. We conclude that Drp1-mediated increases in myocardial ROS production and impairment of mitochondrial calcium handling are key mechanisms of IR injury. Short-term inhibition of Drp1 is a promising strategy to limit early myocardial IR injury which is relevant for the therapy of acute myocardial infarction, cardiac arrest, and heart transplantation.

DOI: https://doi.org/10.1096/fj.202301040RR
G3 (Bethesda). 2023 Dec 21. pii: jkad272. [Epub ahead of print]

Gene dosage adaptations to mtDNA depletion and mitochondrial protein stress in budding yeast.

Joshua T McNamara, Jin Zhu, Yuhao Wang, Rong Li.

  Mitochondria contain a local genome (mtDNA) comprising a small number of genes necessary for respiration, mitochondrial transcription and translation, and other vital functions. Various stressors can destabilize mtDNA leading to mtDNA loss. While some cells can survive mtDNA loss, they exhibit various deficiencies. Here, we investigated the impact of proteotoxicity on mitochondrial function by inducing mitochondrial unfolded protein stress in budding yeast. This led to rapid mtDNA loss, but aerobic conditioning imparted transient resistance to mitochondrial protein stress. We present a quantitative model of mtDNA loss in a growing cell population and measure its parameters. To identify genetic adaptations to mtDNA depletion, we performed a genome-wide screen for gene dosage increases that affect the growth of cells lacking mtDNA. The screen revealed a set of dosage suppressors that alleviate the growth impairment in mtDNA-deficient cells. Additionally, we show that these suppressors of mtDNA stress both bolster cell proliferation and prevent mtDNA loss during mitochondrial protein stress.

Keywords:  copy number variation; functional genomics; mitochondria; mtDNA; protein aggregates; proteostasis; respiration; stress resistance

DOI:  https://doi.org/10.1093/g3journal/jkad272
Antioxidants (Basel). 2023 Dec 13. pii: 2105. [Epub ahead of print]12(12):

Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.

Flores Martín-Reyes, Manuel Bernal, Cristina Rodríguez-Díaz, Damaris Rodríguez-de Los Reyes, Ailec Ho-Plagaro, Francisca Rodríguez-Pacheco, Laura Camacho-Martel, Raquel Camargo-Camero, Francisco J Rodríguez-González, Guillermo Alcain-Martínez, Rafael Martín-Masot, Víctor M Navas-López, Marina Villanueva-Paz, María Isabel Lucena, Eduardo García-Fuentes, Carlos López-Gómez.

  Inflammatory Bowel Diseases (IBD) are a group of chronic, inflammatory disorders of the gut. The incidence and activity of IBD are determined by both genetic and environmental factors. Among these factors, polymorphisms in genes related to autophagy and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have been consistently associated with IBD. We show that NSAIDs induce mitochondrial stress and mitophagy in intestinal epithelial cells. In an altered mitophagy context simulating that observed in IBD patients, NSAID-induced mitochondrial stress leads to the release of mitochondrial components, which act as Danger Associated Molecular Patterns with pro-inflammatory potential. Furthermore, colonic organoids from Crohn's disease patients and healthy donors show activation of the mitochondrial Unfolded Protein Response (UPRmt) upon treatment with ibuprofen. Finally, colon biopsies from Crohn's disease patients in remission or with low-to-moderate activity also show expression of genes involved in UPRmt, while patients with severe activity show no increase compared to healthy donors. Our results suggest the involvement of mitochondria in the mechanisms triggering inflammation in IBD after NSAID use. Moreover, our results highlight the clinical relevance of mitochondrial stress and activation of the UPRmt pathway in the pathophysiology of Crohn's disease.

Keywords:  Crohn’s disease; inflammatory bowel diseases; mitochondria; mitochondrial unfolded protein response; non-steroidal anti-inflammatory drugs

DOI:  https://doi.org/10.3390/antiox12122105
FEMS Yeast Res. 2023 Dec 21. pii: foad054. [Epub ahead of print]

Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions.

Mayuko Hayashi, Tomoyuki Kawarasaki, Kunio Nakatsukasa.

  Most nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. In recent years, the quality control mechanisms of non-imported mitochondrial proteins have been intensively studied. In a previous study, we established that in budding yeast a mutant form of citrate synthase 1 (N∆Cit1) that lacks the N-terminal mitochondrial targeting sequence and therefore mislocalizes to the cytosol is targeted for proteasomal degradation by the SCFUcc1 ubiquitin ligase complex. Here, we show that Hsp70 and Hsp40 chaperones (Ssa1 and Ydj1 in yeast, respectively) are required for N∆Cit1 degradation under heat stress conditions. In the absence of Hsp70 function, a portion of N∆Cit1-GFP formed insoluble aggregates and cytosolic foci. However, the extent of ubiquitination of N∆Cit1 was unaffected, implying that Hsp70/Hsp40 chaperones are involved in the post-ubiquitination step of N∆Cit1 degradation. Intriguingly, degradation of cytosolic/peroxisomal gluconeogenic citrate synthase (Cit2), an endogenous substrate for SCFUcc1-mediated proteasomal degradation, was not highly dependent on Hsp70 even under heat stress conditions. These results suggest that mitochondrial citrate synthase is thermally vulnerable in the cytosol, where Hsp70/Hsp40 chaperones are required to facilitate its degradation.

Keywords:   Saccharomyces cerevisiae ; Hsp70; TCA cycle; citrate synthase; degradation; glyoxylate cycle; ubiquitin-proteasome system

DOI:  https://doi.org/10.1093/femsyr/foad054
Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.

Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.

  Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.

Keywords:  ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response

DOI:  https://doi.org/10.3390/ijms242417423
Eur J Pharmacol. 2023 Dec 19. pii: S0014-2999(23)00806-3. [Epub ahead of print]963 176292

Melatonin protects against myocardial ischemia-reperfusion injury by inhibiting excessive mitophagy through the Apelin/SIRT3 signaling axis.

Zhaoqi Wang, Duomao Lin, Boqun Cui, Dongni Zhang, Jinjing Wu, Jun Ma.

  Excessive or uncontrolled mitophagy may result in a drastic shortage of healthy mitochondrial for ATP supply after reperfusion, leading to irreversible myocardial damage. Melatonin, a hormone produced by the pineal gland, has been proven to ameliorate myocardial ischemia-reperfusion (I/R) injury via regulating mitophagy. However, its underlying mechanism has not been fully elucidated. The present study focused on the role of mitophagy in the cardioprotective effects of melatonin by using the myocardial I/R rat model. The rats were pretreated with or without the apelin inhibitor ML221, the sirtuin 3 (SIRT3) inhibitor 3-TYP and then subjected to I/R injury, with melatonin administrated 10 min before reperfusion. The effects of melatonin on myocardial infarct size, biomarkers of myocardial injury, oxidative stress, and mitochondrial function were detected, and the expression of apelin, SIRT3, and mitophagy-related proteins were also measured. Excessive mitophagy was activated after I/R injury and was correlated with oxidative stress and mitochondrial dysfunction. Melatonin pretreatment ameliorated myocardial injury by decreasing oxidative stress, restoring mitochondrial function, and inhibiting excessive mitophagy. However, ML221 or 3-TYP disrupted these beneficial effects of melatonin on I/R injury. Taken together, these results suggest that melatonin pretreatment ameliorates myocardial I/R injury through regulating the apelin/SIRT3 pathway to inhibit excessive mitophagy.

Keywords:  Apelin; Melatonin; Mitophagy; Myocardial ischemia-reperfusion injury; SIRT3

DOI:  https://doi.org/10.1016/j.ejphar.2023.176292
Int J Mol Sci. 2023 Dec 07. pii: 17209. [Epub ahead of print]24(24):

Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes.

Eirini Taouktsi, Eleni Kyriakou, Evangelia Voulgaraki, Dimitris Verganelakis, Stefania Krokou, Stamatis Rigas, Gerassimos E Voutsinas, Popi Syntichaki.

  p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPKmt), but its functional role still remains elusive. Here, we demonstrate the induction of MAPKmt in worms deficient in the lonp-1 gene, which encodes the worm ortholog of mammalian mitochondrial LonP1. This induction is subjected to negative regulation by the ATFS-1 transcription factor through the CREB-binding protein (CBP) ortholog CBP-3, indicating an interplay between both activated MAPKmt and mitochondrial Unfolded Protein Response (UPRmt) surveillance pathways. Our results also reveal a genetic interaction in lonp-1 mutants between PMK-3 kinase and the ZIP-2 transcription factor. ZIP-2 has an established role in innate immunity but can also modulate the lifespan by maintaining mitochondrial homeostasis during ageing. We show that in lonp-1 animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of zip-2 or pmk-3 shortens the lifespan of lonp-1 mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of pmk-3 specifically diminished the extreme heat tolerance of lonp-1 worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation.

Keywords:  C. elegans; LONP-1; PMK-3; ZIP-2; ageing; heat stress response; mitochondria

DOI:  https://doi.org/10.3390/ijms242417209
Phytomedicine. 2023 Dec 02. pii: S0944-7113(23)00606-2. [Epub ahead of print]123 155247

Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis.

Minmin Gong, Yujin Guo, Hui Dong, Fan Wu, Qiongyao He, Jing Gong, Fuer Lu.

  BACKGROUND: Mitochondrial dysfunction is implicated in the progression of diabetic kidney disease (DKD). Damaged mitochondria produce excessive reactive oxygen species (ROS) that can cause apoptosis. Mitochondrial dynamics control the quality and function of mitochondria. Targeting mitochondrial dynamics may reduce ROS-induced apoptosis and improve renal injury in DKD. Modified Hu-lu-ba-wan (MHLBW) shows distinct clinical effects on DKD patients, which are related to its role in antioxidant stress modulation. However, the relevant mechanisms of MHLBW have not been clearly explored.PURPOSE: This study was aimed to evaluate the therapeutic effects of MHLBW on spontaneous DKD mice and clarify the potential mechanisms.
METHODS: The main components of MHLBW were identified by HPLC. Using db/db mice as DKD models, we evaluated the therapeutic effects of MHLBW on mice after an 8-week administration. We investigated the molecular mechanism of MHLBW in regulating mitochondrial dynamic homeostasis, podocyte apoptosis, and glomerular damage. After that, computational docking analysis and in vitro experiments were conducted for further mechanism verification.
RESULTS: Intragastric administration of MHLBW for 8 weeks in db/db mice significantly improved glucose metabolism, basement membrane thickening, mesangial expansion, glomerular fibrosis, and podocyte injury. MHLBW can reverse podocyte apoptosis via promoting mitochondrial dynamic homeostasis, which was related to regulating the PKM2/ PGC-1α/Opa1 pathway. Berberine (BBR), one of the components of MHLBW, exhibited preeminent affinity with PKM2 as reflected by computational docking analysis. In cultured podocytes, BBR can also prevent apoptosis by promoting PKM2-mediated mitochondrial dynamic homeostasis.
CONCLUSION: Our study demonstrates that MHLBW can treat DKD by inhibiting glomerular damage and podocyte apoptosis through positive regulation of PKM2-mediated mitochondrial dynamic homeostasis. These results may provide a potential strategy against DKD.

Keywords:  Diabetic kidney disease; Mitochondrial dynamic homeostasis; Modified Hu-lu-ba-wan; PKM2; Podocyte

DOI:  https://doi.org/10.1016/j.phymed.2023.155247
Leukemia. 2023 Dec 15.

DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.

Jean-François Spinella, Jalila Chagraoui, Céline Moison, Vincent P Lavallée, Isabel Boivin, Deanne Gracias, Sylvie Lavallée, Guillaume Richard Carpentier, François Beliveau, Josée Hébert, Guy Sauvageau.

Monosomy 5 and deletions of the chromosome 5q (-5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 -5/del(5q) patient specimens and 367 control AML, we identified DELE1 - located in the common deleted region - as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in -5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in -5/del(5q) AML.

DOI: https://doi.org/10.1038/s41375-023-02107-4
Cells. 2023 Dec 07. pii: 2781. [Epub ahead of print]12(24):

Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.

Tian Liu, Liam Wetzel, Zexi Zhu, Pavan Kumaraguru, Viraj Gorthi, Yan Yan, Mohammed Zaheen Bukhari, Aizara Ermekbaeva, Hanna Jeon, Teresa R Kee, Jung-A Alexa Woo, David E Kang.

  Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) is a nuclear-encoded mitochondrial protein which is primarily mutated in the spectrum of familial and sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD). Endogenous CHCHD10 levels decline in the brains of ALS-FTD patients, and the CHCHD10S59L mutation in Drosophila induces dominant toxicity together with PTEN-induced kinase 1 (PINK1), a protein critical for the induction of mitophagy. However, whether and how CHCHD10 variants regulate mitophagy flux in the mammalian brain is unknown. Here, we demonstrate through in vivo and in vitro models, as well as human FTD brain tissue, that ALS/FTD-linked CHCHD10 mutations (R15L and S59L) impair mitophagy flux and mitochondrial Parkin recruitment, whereas wild-type CHCHD10 (CHCHD10WT) normally enhances these measures. Specifically, we show that CHCHD10R15L and CHCHD10S59L mutations reduce PINK1 levels by increasing PARL activity, whereas CHCHD10WT produces the opposite results through its stronger interaction with PARL, suppressing its activity. Importantly, we also demonstrate that FTD brains with TAR DNA-binding protein-43 (TDP-43) pathology demonstrate disruption of the PARL-PINK1 pathway and that experimentally impairing mitophagy promotes TDP-43 aggregation. Thus, we provide herein new insights into the regulation of mitophagy and TDP-43 aggregation in the mammalian brain through the CHCHD10-PARL-PINK1 pathway.

Keywords:  CHCHD10; PARL; PINK1; TDP-43; mitophagy

DOI:  https://doi.org/10.3390/cells12242781