bims-mikwok 2024-02-04 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–02–04
twenty-one papers selected by
Gavin McStay, Liverpool John Moores University

Aberrant mitochondrial aggregation of TDP-43 activated mitochondrial unfolded protein response and contributed to recovery of acetaminophen induced acute liver injury.
ULP-2 SUMO protease regulates UPRmt and mitochondrial homeostasis in Caenorhabditis elegans.
Mitochondrial protein synthesis quality control.
Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.
Mitophagy in plants: Emerging regulators of mitochondrial targeting for selective autophagy.
Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
Optineurin provides a mitophagy contact site for TBK1 activation.
Rhein alleviates myocardial ischemic injury by inhibiting mitochondrial division, activating mitochondrial autophagy and suppressing myocardial cell apoptosis through the Drp1/Pink1/Parkin pathway.
Collagen I protects human keratinocytes HaCaT against UVB injury via restoring PINK1/parkin-mediated mitophagy.
Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics.
Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.
The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control.
Mitophagy Activation by Rapamycin Enhances Mitochondrial Function and Cognition in 5×FAD Mice.
Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.
OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria.
Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6.
Leukemia and mitophagy: a novel perspective for understanding oncogenesis and resistance.
Caffeic acid activates mitochondrial UPR to resist pathogen infection in Caenorhabditis elegans via the transcription factor ATFS-1.
Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1-mediated axon degeneration.
Acetyl-CoA production by octanoic acid alleviates acute compartment syndrome-induced skeletal muscle injury through regulating mitophagy.
Recent insights into the control of mitochondrial fission.

Toxicol Res (Camb). 2024 Feb;13(1): tfae008

Aberrant mitochondrial aggregation of TDP-43 activated mitochondrial unfolded protein response and contributed to recovery of acetaminophen induced acute liver injury.

Zhaoxiong Liu, Yalong Qiang, Shulin Shan, Shuai Wang, Zhidan Liu, Yiyu Yang, Zhengcheng Huang, Mingxue Song, Xiulan Zhao, Fuyong Song.

  Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.

Keywords:  TDP-43; drug induced liver injury; mitochondrial injury; mitochondrial unfolded protein response

DOI:  https://doi.org/10.1093/toxres/tfae008
Free Radic Biol Med. 2024 Jan 30. pii: S0891-5849(24)00058-3. [Epub ahead of print]

ULP-2 SUMO protease regulates UPRmt and mitochondrial homeostasis in Caenorhabditis elegans.

Lirin Michaeli, Eyal Spector, Simon Haeussler, Cátia A Carvalho, Hanna Grobe, Ulrike Bening Abu-Shach, Hen Zinger, Barbara Conradt, Limor Broday.

  Mitochondria are the powerhouses of cells, responsible for energy production and regulation of cellular homeostasis. When mitochondrial function is impaired, a stress response termed mitochondrial unfolded protein response (UPRmt) is initiated to restore mitochondrial function. Since mitochondria and UPRmt are implicated in many diseases, it is important to understand UPRmt regulation. In this study, we show that the SUMO protease ULP-2 has a key role in regulating mitochondrial function and UPRmt. Specifically, down-regulation of ulp-2 suppresses UPRmt and reduces mitochondrial membrane potential without significantly affecting cellular ROS. Mitochondrial networks are expanded in ulp-2 null mutants with larger mitochondrial area and increased branching. Moreover, the amount of mitochondrial DNA is increased in ulp-2 mutants. Downregulation of ULP-2 also leads to alterations in expression levels of mitochondrial genes involved in protein import and mtDNA replication, however, mitophagy remains unaltered. In summary, this study demonstrates that ULP-2 is required for mitochondrial homeostasis and the UPRmt.

Keywords:  Mitochondrial unfolded protein response; SENP; SUMO; SUMO protease; Smo-1; ULP-2; UPRm

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.050
Hum Mol Genet. 2024 Jan 27. pii: ddae012. [Epub ahead of print]

Mitochondrial protein synthesis quality control.

Lidiia Koludarova, Brendan J Battersby.

  Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.

Keywords:  AFG3L2; MTRFR; OMA1; OPA1; OXA1L; RNA processing; cell stress; co-translational quality control; fusion open reading frames; membrane morphology; mitochondria; non-stop mRNA; post-transcriptional; protein synthesis; proteostasis; ribosome quality control; ribosomes

DOI:  https://doi.org/10.1093/hmg/ddae012
Cell Regen. 2024 Jan 31. 13(1): 2

Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.

Xinhang Li, Yalin Zhu, Pilar Ruiz-Lozano, Ke Wei.

  The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.

Keywords:  ATF4; Cardiomyocyte; Cpt1b; FAO; H3k4me3; Mitochondria; Mrps5; Proliferation; UPRmt; αKG

DOI:  https://doi.org/10.1186/s13619-024-00186-x
J Microsc. 2024 Jan 31.

Mitophagy in plants: Emerging regulators of mitochondrial targeting for selective autophagy.

Patrick J Duckney, Pengwei Wang, Patrick J Hussey.

  The degradation and turnover of mitochondria is fundamental to Eukaryotes and is a key homeostatic mechanism for maintaining functional mitochondrial populations. Autophagy is an important pathway by which mitochondria are degraded, involving their sequestration into membrane-bound autophagosomes and targeting to lytic endosomal compartments (the lysosome in animals, the vacuole in plants and yeast). Selective targeting of mitochondria for autophagy, also known as mitophagy, distinguishes mitochondria from other cell components for degradation and is necessary for the regulation of mitochondria-specific cell processes. In mammals and yeast, mitophagy has been well characterised and is regulated by numerous pathways with diverse and important functions in the regulation of cell homeostasis, metabolism and responses to specific stresses. In contrast, we are only just beginning to understand the importance and functions of mitophagy in plants, chiefly as the proteins that target mitochondria for autophagy in plants are only recently emerging. Here, we discuss the current progress of our understanding of mitophagy in plants, the importance of mitophagy for plant life and the regulatory autophagy proteins involved in mitochondrial degradation. In particular, we will discuss the recent emergence of mitophagy receptor proteins that selectively target mitochondria for autophagy, and discuss the missing links in our knowledge of mitophagy-regulatory proteins in plants compared to animals and yeast.

Keywords:  Arabidopsis; TRB1; TraB; autophagy; contact site; homeostasis; mitochondria; mitophagy; plant; stress

DOI:  https://doi.org/10.1111/jmi.13267
Nat Commun. 2024 Jan 27. 15(1): 830

Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.

Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.

DOI: https://doi.org/10.1038/s41467-024-45044-1
EMBO J. 2024 Jan 29.

Optineurin provides a mitophagy contact site for TBK1 activation.

Koji Yamano, Momoha Sawada, Reika Kikuchi, Kafu Nagataki, Waka Kojima, Ryu Endo, Hiroki Kinefuchi, Atsushi Sugihara, Tomoshige Fujino, Aiko Watanabe, Keiji Tanaka, Gosuke Hayashi, Hiroshi Murakami, Noriyuki Matsuda.

  Tank-binding kinase 1 (TBK1) is a Ser/Thr kinase that is involved in many intracellular processes, such as innate immunity, cell cycle, and apoptosis. TBK1 is also important for phosphorylating the autophagy adaptors that mediate the selective autophagic removal of damaged mitochondria. However, the mechanism by which PINK1-Parkin-mediated mitophagy activates TBK1 remains largely unknown. Here, we show that the autophagy adaptor optineurin (OPTN) provides a unique platform for TBK1 activation. Both the OPTN-ubiquitin and the OPTN-pre-autophagosomal structure (PAS) interaction axes facilitate assembly of the OPTN-TBK1 complex at a contact sites between damaged mitochondria and the autophagosome formation sites. At this assembly point, a positive feedback loop for TBK1 activation is initiated that accelerates hetero-autophosphorylation of the protein. Expression of monobodies engineered here to bind OPTN impaired OPTN accumulation at contact sites, as well as the subsequent activation of TBK1, thereby inhibiting mitochondrial degradation. Taken together, these data show that a positive and reciprocal relationship between OPTN and TBK1 initiates autophagosome biogenesis on damaged mitochondria.

Keywords:  Autophagy; Mitochondria; PINK1; Parkin; Ubiquitin

DOI:  https://doi.org/10.1038/s44318-024-00036-1
Mol Biol Rep. 2024 Feb 01. 51(1): 266

Rhein alleviates myocardial ischemic injury by inhibiting mitochondrial division, activating mitochondrial autophagy and suppressing myocardial cell apoptosis through the Drp1/Pink1/Parkin pathway.

Hanqing Li, Yan Jia, Daomin Yao, Ming Gao, Lijun Wang, Jing Liu.

   BACKGROUND: Rhein, which has antioxidant and anti-inflammatory response properties, is a beneficial treatment for different pathologies. However, the mechanism by which rhein protects against myocardial ischemic injury is poorly understood.
METHODS AND RESULTS: To establish an acute myocardial infarction (AMI) rat model, we performed left anterior descending (LAD) ligation. Sprague‒Dawley rats were randomly divided into four groups: sham, AMI, AMI + rhein (AMI + R), and AMI + mitochondrial fission inhibitor (AMI + M). The extent of myocardial injury was evaluated by TTC staining, serum myocardial injury markers, and HE and Masson staining. Cardiac mitochondria ultrastructure was visualized by transmission electron microscopy. TUNEL assay and flow cytometry analysis were used to estimate cell apoptosis. Protein expression levels were measured by Western blotting. In vitro, the efficacy of rhein was assessed in H9c2 cells under hypoxic condition. Our results revealed that rats with AMI exhibited increased infarct size and indicators of myocardial damage, along with activation of Drp1-dependent mitochondrial fission, decreased mitophagy and increased apoptosis rates. However, pretreatment with rhein significantly reversed these effects and demonstrated similar efficacy to Mdivi-1. Furthermore, rhein pretreatment protected against myocardial ischemic injury by inhibiting mitochondrial fission, as evidenced by decreased Drp1 expression. It also enhanced mitophagy, as indicated by increased expression of Beclin1, Pink1 and Parkin, an increased LC3-II/LC3-I ratio and increased formation of autolysosomes. Additionally, rhein pretreatment mitigated apoptosis in AMI. These results were also confirmed in vitro in H9c2 cells.
CONCLUSION: Our results demonstrate that rhein pretreatment exerts cardioprotective effects against myocardial ischemic injury via the Drp1/Pink1/Parkin pathway.

Keywords:  Acute myocardial infarction; Apoptosis; Mitochondrial fission; Mitophagy; Rhein; Traditional Chinese medicine

DOI:  https://doi.org/10.1007/s11033-023-09154-1
Arch Biochem Biophys. 2024 Jan 26. pii: S0003-9861(24)00024-9. [Epub ahead of print]753 109905

Collagen I protects human keratinocytes HaCaT against UVB injury via restoring PINK1/parkin-mediated mitophagy.

Yuying Zhu, Wendie Xiang, Sijun He, Zhao San, Weiwei Liu, Jin Wu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.

  Collagen I is a major component of extracellular matrix in human skin, and is also widely used in a variety of skin-care products. In this study, we investigated the modulatory roles of collagen I on human immortalized keratinocytes HaCaT, especially when cells were irradiated with UVB. Interestingly, the cells grown on plates coated by molecular collagen I, but not fibrillar collagen I, acquired certain resistance against UVB damages, as shown by increased survival and reduced apoptosis. The accumulation of dysfunctional mitochondria in UVB-treated cells was attenuated by molecular collagen I-coating. Interestingly, molecular collagen I rescued the loss of mitochondrial biogenesis in cells treated with UVB. Loss of PINK1/parkin-mediated mitophagy was dominant for the accumulation of dysfunctional mitochondria after UVB irradiation. Of note, cells cultured on molecular collagen I-precoated plates exhibited reserved mitophagy after UVB irradiation, as reflected by the enhanced protein level of PINK1/parkin, increased mitochondrial ubiquitin and the co-localization of lysosomes and mitochondria. Moreover, in UVB-treated cells, inhibiting mitophagy by Cyclosporin A, or by silencing PINK1 or parkin, disturbed the resolution of mitochondrial stress and reduced the protective effect of molecular collagen I, indicating that mitophagy is pivotal for the protection of collagen I against UVB damage in keratinocytes HaCaT. Collectively, this study reveals an unexpected protective role of collagen I, which facilitates mitophagy to rescue cells under UVB irradiation, providing a new direction for clinical application of collagen products.

Keywords:  Apoptosis; Collagen I; HaCaT cells; Mitophagy; UVB

DOI:  https://doi.org/10.1016/j.abb.2024.109905
Redox Biol. 2024 Jan 20. pii: S2213-2317(24)00025-9. [Epub ahead of print]70 103049

Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics.

Marissa D Pokharel, Alejandro Garcia-Flores, David Marciano, Maria C Franco, Jeffrey R Fineman, Saurabh Aggarwal, Ting Wang, Stephen M Black.

  Once thought of in terms of bioenergetics, mitochondria are now widely accepted as both the orchestrator of cellular health and the gatekeeper of cell death. The pulmonary disease field has performed extensive efforts to explore the role of mitochondria in regulating inflammation, cellular metabolism, apoptosis, and oxidative stress. However, a critical component of these processes needs to be more studied: mitochondrial network dynamics. Mitochondria morphologically change in response to their environment to regulate these processes through fusion, fission, and mitophagy. This allows mitochondria to adapt their function to respond to cellular requirements, a critical component in maintaining cellular homeostasis. For that reason, mitochondrial network dynamics can be considered a bridge that brings multiple cellular processes together, revealing a potential pathway for therapeutic intervention. In this review, we discuss the critical modulators of mitochondrial dynamics and how they are affected in pulmonary diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), and pulmonary arterial hypertension (PAH). A dysregulated mitochondrial network plays a crucial role in lung disease pathobiology, and aberrant fission/fusion/mitophagy pathways are druggable processes that warrant further exploration. Thus, we also discuss the candidates for lung disease therapeutics that regulate mitochondrial network dynamics.

Keywords:  Mitochondrial function; Mitochondrial remodeling; Mitophagy; Pulmonary disease

DOI:  https://doi.org/10.1016/j.redox.2024.103049
Free Radic Biol Med. 2024 Jan 26. pii: S0891-5849(24)00043-1. [Epub ahead of print]213 394-408

Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.

Bixi Gao, Zongqi Wang, Kun Dai, Yunjiang Wang, Longyuan Li, Guangzhao Li, Xiaowang Niu, Xiang Li, Zhengquan Yu, Zhong Wang, Gang Chen.

   BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt.
METHODS: Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression.
RESULTS: The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo.
CONCLUSIONS: We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.

Keywords:  Acetylation; Glioblastoma; GrpEL1; UPRmt; mtHSP70

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.035
Sci Rep. 2024 01 29. 14(1): 2354

The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control.

Soh Yamamoto, Noriko Ogasawara, Yukari Mitsuhashi, Kenichi Takano, Shin-Ichi Yokota.

The mechanism underlying the anti-inflammatory effect of macrolide antibiotics, such as clarithromycin (CAM), remains to be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25 (SNAP25)-like protein homolog (NIPSNAP) 1 and 2 are involved in the immune response and mitochondrial homeostasis. However, the axis between CAM-NIPSNAP-mitochondria and Toll-like receptor (TLR) and their molecular mechanisms remain unknown. In this study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by NIPSNAP1 and 2 and the immunomodulatory effect of CAM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8) production. Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was not impaired in NIPSNAP1 and 2 individual knockout (KO) and double KO (DKO) cells. Moreover, the oxygen consumption rate (OCR) in mitochondria measured using a flex analyzer was significantly reduced in NIPSNAP1 or 2 KD cells, but not in DKO cells. CAM also dose-dependently reduced the OCR. These results indicate that CAM suppresses the IL-8 production via the mitochondrial quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomodulatory effects of macrolides.

DOI: https://doi.org/10.1038/s41598-024-52582-7
Behav Brain Res. 2024 Jan 30. pii: S0166-4328(24)00045-7. [Epub ahead of print] 114889

Mitophagy Activation by Rapamycin Enhances Mitochondrial Function and Cognition in 5×FAD Mice.

Wenrong Zheng, Kualiang Li, Meihua Zhong, Kejun Wu, Lele Zhou, Jie Huang, Libin Liu, Zhou Chen.

  Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by severe mitochondrial dysfunction, which is an intracellular process that is significantly compromised in the early stages of AD. Mitophagy, the selective removal of damaged mitochondria, is a potential therapeutic strategy for AD. Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, augmented autophagy and mitigated cognitive impairment. Our study revealed that rapamycin enhances cognitive function by activating mitophagy, alleviating neuronal loss, and improving mitochondrial dysfunction in 5×FAD mice. Interestingly, the neuroprotective effect of rapamycin in AD were negated by treatment with 3-MA, a mitophagy inhibitor. Overall, our findings suggest that rapamycin ameliorates cognitive impairment in 5×FAD mice via mitophagy activation and its downstream PINK1-Parkin pathway, which aids in the clearance of amyloid-β (Aβ) and damaged mitochondria. This study reveals a novel mechanism involving mitophagy regulation underlying the therapeutic effect of rapamycin in AD. This study provides new insights and therapeutic targets for rapamycin in the treatment of AD. However, there are still some shortcomings in this topic; if we can further knock out the PINK1/Parkin gene in animals or use siRNA technology, we can further confirm the experimental results.

Keywords:  5×FAD mice; Cognitive impairment; Mitochondrial dysfunction; Mitophagy; Rapamycin

DOI:  https://doi.org/10.1016/j.bbr.2024.114889
Nat Metab. 2024 Jan 29.

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.

Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey E Rhyne, Jiaxin Qian, Chao-Wei Hung, Peng Zhao, Ying Jones, Hui Gao, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Mikael Rydén, Martin Wabitsch, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg, Shannon M Reilly, Jianfeng Huang, Alan R Saltiel.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

DOI: https://doi.org/10.1038/s42255-024-00978-0
bioRxiv. 2024 Jan 20. pii: 2024.01.17.576115. [Epub ahead of print]

OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria.

Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, John A Collins, Makarand V Risbud.

Due to their glycolytic nature and limited vascularity, nucleus pulposus (NP) cells of the intervertebral disc and articular chondrocytes were long thought to have minimal reliance on mitochondrial function. Recent studies have challenged this long-held view and highlighted the increasingly important role of mitochondria in the physiology of these tissues. We investigated the role of mitochondrial fusion protein OPA1 in maintaining the spine and knee joint health in aging mice. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate without affecting ATP synthesis. OPA1 governed the morphology of multiple organelles, and its loss resulted in the dysregulation of NP cell autophagy. Metabolic profiling and 13 C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1 AcanCreERT2 mice showed age- dependent disc, and cartilage degeneration and vertebral osteopenia. Our findings suggest that OPA1 regulation of mitochondrial dynamics and multi-organelle interactions is critical in preserving metabolic homeostasis of disc and cartilage.
Teaser: OPA1 is necessary for the maintenance of intervertebral disc and knee joint health in aging mice.

DOI: https://doi.org/10.1101/2024.01.17.576115
Acta Neuropathol. 2024 Jan 29. 147(1): 26

Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6.

Tsz Chui Sophia Leung, Eviatar Fields, Namrata Rana, Ru Yi Louisa Shen, Alexandra E Bernstein, Anna A Cook, Daniel E Phillips, Alanna J Watt.

  Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset.

Keywords:  Ataxia; Disease progression; Metabolomics; Mitochondria; Purkinje cell; Transcriptome

DOI:  https://doi.org/10.1007/s00401-023-02680-z
Ann Hematol. 2024 Jan 29.

Leukemia and mitophagy: a novel perspective for understanding oncogenesis and resistance.

Yueyao Liu, Zhigui Ma.

  Mitophagy, the selective autophagic process that specifically degrades mitochondria, serves as a vital regulatory mechanism for eliminating damaged mitochondria and maintaining cellular balance. Emerging research underscores the central role of mitophagy in the initiation, advancement, and treatment of cancer. Mitophagy is widely acknowledged to govern mitochondrial homeostasis in hematopoietic stem cells (HSCs), influencing their metabolic dynamics. In this article, we integrate recent data to elucidate the regulatory mechanisms governing mitophagy and its intricate significance in the context of leukemia. An in-depth molecular elucidation of the processes governing mitophagy may serve as a basis for the development of pioneering approaches in targeted therapeutic interventions.

Keywords:  Autophagy; HSCs; Leukemia; Mitophagy; Resistance; Therapy

DOI:  https://doi.org/10.1007/s00277-024-05635-w
Infect Immun. 2024 Jan 31. e0049423

Caffeic acid activates mitochondrial UPR to resist pathogen infection in Caenorhabditis elegans via the transcription factor ATFS-1.

Yi Xiao, Cao-An Hong, Fang Liu, Dandan Shi, Xinting Zhu, Changyan Yu, Nian Jiang, Sanhua Li, Yun Liu.

  Mitochondria play roles in the resistance of Caenorhabditis elegans against pathogenic bacteria by regulating mitochondrial unfolded protein response (UPRmt). Caffeic acid (CA) (3,4-dihydroxy cinnamic acid) is a major phenolic compound present in several plant species, which exhibits biological activities such as antioxidant, anti-fibrosis, anti-inflammatory, and anti-tumor properties. However, whether caffeic acid influences the innate immune response and the underlying molecular mechanisms remains unknown. In this study, we find that 20 µM caffeic acid enhances innate immunity to resist the Gram-negative pathogen Pseudomonas aeruginosa infection in C. elegans. Meanwhile, caffeic acid also inhibits the growth of pathogenic bacteria. Furthermore, caffeic acid promotes host immune response by reducing the bacterial burden in the intestine. Through genetic screening in C. elegans, we find that caffeic acid promotes innate immunity via the transcription factor ATFS-1. In addition, caffeic acid activates the UPRmt and immune response genes for innate immune response through ATFS-1. Our work suggests that caffeic acid has the potential to protect patients from pathogen infection.

Keywords:  Caenorhabditis elegans; caffeic acid; innate immunity; mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1128/iai.00494-23
J Neurosci Res. 2024 Jan;102(1): e25292

Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1-mediated axon degeneration.

Shuai Wang, Yifan Zhang, Mingxue Song, Xiulan Zhao, Fuyong Song.

  Autophagic dysfunction in neurodegenerative diseases is being extensively studied, yet the exact mechanism of macroautophagy/autophagy in axon degeneration is still elusive. A recent study by Kim et al. links autophagic stress to the sterile α and toll/interleukin 1 receptor motif containing protein 1 (SARM1)-dependent core axonal degeneration program, providing a new insight into the role of autophagy in axon degeneration. In the classical Wallerian axon degeneration model of axotomy, disruption of axonal transport destroys the coordinated activity of pro-survival and pro-degenerative factors in the axoplasm and activates the NADase activity of SARM1, thus triggering the axonal self-destruction program. However, the mechanism for SARM1 activation in the chronic neurodegenerative disorders is more complex. Mitochondrial defects and oxidative stress contribute to the activation of SARM1, while mitophagy can inhibit mitochondrial dysfunction and promote the clearance of SARM1 on mitochondria, thus protecting against neuronal degeneration. Therefore, in-depth elucidation of the underlying mechanisms of mitophagy during axonal degeneration can help develop promising strategies for the prevention and treatment of various neurodegenerative disorders.

Keywords:  SARM1; autophagy; axon degeneration; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.1002/jnr.25292
Shock. 2024 Jan 08.

Acetyl-CoA production by octanoic acid alleviates acute compartment syndrome-induced skeletal muscle injury through regulating mitophagy.

Xiangkang Jiang, Shaoyun Liu, Jingyuan Yang, Yao Lin, Wenbin Zhang, Jiawei Tao, Huiming Zhong, Jiefeng Xu, Mao Zhang.

BACKGROUND: Treatment of acute compartment syndrome (ACS) induced skeletal muscle injury remains a challenge. Previous studies have shown that octanoic acid is a promising treatment for ACS owing to its potential ability to regulate metabolic/epigenetic pathways in ischemic injury. The present study was designed to investigate the efficacy and underlying mechanism of octanoic acid in ACS-induced skeletal muscle injury.
METHODS: In this study, we established a saline infusion ACS rat model. Subsequently, we assessed the protective effects of sodium octanoate (NaO, sodium salt of octanoic acid) on ACS-induced skeletal muscle injury. Afterward, the level of acetyl-CoA and histone acetylation in the skeletal muscle tissue were quantified. Moreover, we investigated the activation of the AMPK pathway and the occurrence of mitophagy in the skeletal muscle tissue. Lastly, we scrutinized the expression of proteins associated with mitochondrial dynamics in the skeletal muscle tissue.
RESULTS: The administration of NaO attenuated muscle inflammation, alleviating oxidative stress and muscle edema. Moreover, NaO treatment enhanced muscle blood perfusion, leading to the inhibition of apoptosis-related skeletal muscle cell death following ACS. Additionally, NaO demonstrated the ability to halt skeletal muscle fibrosis and enhance the functional recovery of muscle post-ACS. Further analysis indicates that NaO treatment increases the acetyl-CoA level in muscle and the process of histone acetylation by acetyl-CoA. Lastly, we found NaO treatment exerts a stimulatory impact on the activation of the AMPK pathway, thus promoting mitophagy and improving mitochondrial dynamics.
CONCLUSION: Our findings indicate that octanoic acid may ameliorate skeletal muscle injury induced by ACS. Its protective effects may be attributed to the promotion of acetyl-CoA synthesis and histone acetylation within the muscular tissue, as well as its activation of the AMPK-related mitophagy pathway.

DOI: https://doi.org/10.1097/SHK.0000000000002304
Biochem Soc Trans. 2024 Jan 30. pii: BST20230220. [Epub ahead of print]

Recent insights into the control of mitochondrial fission.

Jiajia He, Ke Liu, Chuanhai Fu.

  Mitochondria are the powerhouse of the cell. They undergo fission and fusion to maintain cellular homeostasis. In this review, we explore the intricate regulation of mitochondrial fission at various levels, including the protein level, the post-translational modification level, and the organelle level. Malfunctions in mitochondrial fission can have detrimental effects on cells. Therefore, we also examine the association between mitochondrial fission with diseases such as breast cancer and cardiovascular disorders. We anticipate that a comprehensive investigation into the control of mitochondrial fission will pave the way for the development of innovative therapeutic strategies.

Keywords:  mitochondria; organelles; phosphorylation/dephosphorylation; transmembrane proteins

DOI:  https://doi.org/10.1042/BST20230220