bims-mikwok 2024-07-07 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒07‒07
twenty-one papers selected by
Gavin McStay, Liverpool John Moores University

The germline coordinates mitokine signaling.
Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.
Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
Voltage-dependent anion channel 1 mediates mitochondrial fission and glucose metabolic reprogramming in response to ionizing radiation.
Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing.
Src inhibition modulates AMBRA1-mediated mitophagy to counteract endothelial-to-mesenchymal transition in renal allograft fibrosis.
Insights into the role of mitophagy in lung cancer: current evidence and perspectives.
GTPBP8 plays a role in mitoribosome formation in human mitochondria.
Macrophage migration inhibitory factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury.
IGF2 promotes the differentiation of chicken embryonic myoblast by regulating mitochondrial remodeling.
BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC.
From macroautophagy to mitophagy: Unveiling the hidden role of mitophagy in gastrointestinal disorders.
Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.
MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.
Commentary on the Article "BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy".
Calcium (Ca2+) hemostasis, mitochondria, autophagy, and mitophagy contribute to Alzheimer's disease as early moderators.
Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition: Harnessing the power of nanotheranostics.
Impaired mitochondrial quality control in fibromyalgia: mechanisms involved in skeletal muscle alteration.
Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.
Importance of conserved hydrophobic pocket region in yeast mitoribosomal mL44 protein for mitotranslation and transcript preference.

Cell. 2024 Jun 26. pii: S0092-8674(24)00650-0. [Epub ahead of print]

The germline coordinates mitokine signaling.

Koning Shen, Jenni Durieux, Cesar G Mena, Brant M Webster, C Kimberly Tsui, Hanlin Zhang, Larry Joe, Kristen M Berendzen, Andrew Dillin.

  The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.

Keywords:  C. elegans; aging; germline; lipids; mitochondria; mtUPR; proteostasis; stress response

DOI:  https://doi.org/10.1016/j.cell.2024.06.010
Biomed Pharmacother. 2024 Jul 02. pii: S0753-3322(24)00873-4. [Epub ahead of print]177 116989

Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.

Jinlan Deng, Danyang Wang, Yanmei Shi, Lin Lin, Weihan Gao, Yu Sun, Xiayinan Song, Yunlun Li, Jie Li.

  The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.

Keywords:  Cardiovascular diseases; Factors; Molecular mechanism; UPR(mt)

DOI:  https://doi.org/10.1016/j.biopha.2024.116989
Aging Cell. 2024 Jul 02. e14262

Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.

Annika Traa, Allison Keil, Abdelrahman AlOkda, Suleima Jacob-Tomas, Aura A Tamez González, Shusen Zhu, Zenith Rudich, Jeremy M Van Raamsdonk.

  The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.

Keywords:   C. elegans ; aging; biological resilience; genetics; lifespan; mitochondria; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.1111/acel.14262
PLoS Biol. 2024 Jul;22(7): e3002671

Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.

Noga Preminger, Maya Schuldiner.

Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission and fusion. However, recent research has unveiled an intricate and multifaceted landscape of mitochondrial morphology that extends far beyond the conventional fission-fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse processes influencing mitochondrial shape and network formation, highlighting the intriguing complexities and gaps in our understanding of mitochondrial architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future research in this evolving field.

DOI: https://doi.org/10.1371/journal.pbio.3002671
Sci Total Environ. 2024 Jun 30. pii: S0048-9697(24)04394-8. [Epub ahead of print]946 174246

Voltage-dependent anion channel 1 mediates mitochondrial fission and glucose metabolic reprogramming in response to ionizing radiation.

Ying Xie, Xiaochang Liu, Dafei Xie, Wen Zhang, Hongling Zhao, Hua Guan, Ping-Kun Zhou.

  The ionizing radiation (IR) represents a formidable challenge as an environmental factor to mitochondria, leading to disrupt cellular energy metabolism and posing health risks. Although the deleterious impacts of IR on mitochondrial function are recognized, the specific molecular targets remain incompletely elucidated. In this study, HeLa cells subjected to γ-rays exhibited concomitant oxidative stress, mitochondrial structural alterations, and diminished ATP production capacity. The γ-rays induced a dose-dependent induction of mitochondrial fission, simultaneously manifested by an elevated S616/S637 phosphorylation ratio of the dynamin-related protein 1 (DRP1) and a reduction in the expression of the mitochondrial fusion protein mitofusin 2 (MFN2). Knockdown of DRP1 effectively mitigated γ-rays-induced mitochondrial network damage, implying that DRP1 phosphorylation may act as an effector of radiation-induced mitochondrial damage. The mitochondrial outer membrane protein voltage-dependent anion channel 1 (VDAC1) was identified as a crucial player in IR-induced mitochondrial damage. The VDAC1 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), counteracts the excessive mitochondrial fission induced by γ-rays, consequently rebalancing the glycolytic and oxidative phosphorylation equilibrium. This metabolic shift was uncovered to enhance glycolytic capacity, thus fortifying cellular resilience and elevating the radiosensitivity of cancer cells. These findings elucidate the intricate regulatory mechanisms governing mitochondrial morphology under radiation response. It is anticipated that the development of targeted drugs directed against VDAC1 may hold promise in augmenting the sensitivity of tumor cells to radiotherapy and chemotherapy.

Keywords:  Glucose metabolic reprogramming; Ionizing radiation; Mitochondrial dynamics; Oxidative stress; Voltage-dependent anion channel 1

DOI:  https://doi.org/10.1016/j.scitotenv.2024.174246
Autophagy. 2024 Jul 04. 1-12

Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing.

Diana García-Chávez, Eunice Domínguez-Martín, Laura Kawasaki, Laura Ongay-Larios, Hilario Ruelas-Ramírez, Ariann E Mendoza-Martinez, Juan P Pardo, Soledad Funes, Roberto Coria.

  The prohibitins Phb1 and Phb2 assemble at the mitochondrial inner membrane to form a multi-dimeric complex. These scaffold proteins are highly conserved in eukaryotic cells, from yeast to mammals, and have been implicated in a variety of mitochondrial functions including aging, proliferation, and degenerative and metabolic diseases. In mammals, PHB2 regulates PINK1-PRKN mediated mitophagy by interacting with lipidated MAP1LC3B/LC3B. Despite their high conservation, prohibitins have not been linked to mitophagy in budding yeasts. In this study, we demonstrate that both Phb1 and Phb2 are required to sustain mitophagy in Saccharomyces cerevisiae. Prohibitin-dependent mitophagy requires formation of the Phb1-Phb2 complex and a conserved AIM/LIR-like motif identified in both yeast prohibitins. Furthermore, both Phb1 and Phb2 interact and exhibit mitochondrial colocalization with Atg8. Interestingly, we detected a basal C terminus processing of the mitophagy receptor Atg32 that depends on the presence of the i-AAA Yme1. In the absence of prohibitins this processing is highly enhanced but reverted by the inactivation of the rhomboid protease Pcp1. Together our results revealed a novel role of yeast prohibitins in mitophagy through its interaction with Atg8 and regulating an Atg32 proteolytic event. Abbreviation: AIM/LIR: Atg8-family interacting motif/LC3-interacting region; ANOVA: analysis of variance; ATG/Atg: autophagy related; C terminus/C-terminal: carboxyl terminus/carboxyl-terminal; GFP: green fluorescent protein; HA: human influenza hemagglutinin; Idh1: isocitrate dehydrogenase 1; MAP1C3B/LC3B: microtubule associated protein 1 light chain 3 beta; mCh: mCherry; MIM: mitochondrial inner membrane; MOM: mitochondrial outer membrane; N starvation: nitrogen starvation; N terminus: amino terminus; PARL: presenilin associated rhomboid like; Pcp1: processing of cytochrome c peroxidase 1; PCR: polymerase chain reaction; PGAM5: PGAM family member 5 mitochondrial serine/threonine protein phosphatase; PHBs/Phb: prohibitins; PINK1: PTEN induced kinase 1; PMSF: phenylmethylsulfonyl fluoride; PRKN: parkin RBR E3 ubiquitin protein ligase; SD: synthetic defined medium; SDS: sodium dodecyl sulfate; SMD-N: synthetic defined medium lacking nitrogen; WB: western blot; WT: wild type; Yme1: yeast mitochondrial escape 1; YPD: yeast extract-peptone-dextrose medium; YPLac: yeast extract-peptone-lactate medium.

Keywords:  AIM/LIR motif; PARL; PINK1-PRKN; autophagy; i-AAA protease (Yme1); rhomboid protease (Pcp1)

DOI:  https://doi.org/10.1080/15548627.2024.2371717
Cell Prolif. 2024 Jun 29. e13699

Src inhibition modulates AMBRA1-mediated mitophagy to counteract endothelial-to-mesenchymal transition in renal allograft fibrosis.

Zeping Gui, Xuzhong Liu, Zhen Xu, Dengyuan Feng, Zhou Hang, Ming Zheng, Hao Chen, Shuang Fei, Li Sun, Jun Tao, Zhijian Han, Xiaobin Ju, Min Gu, Ruoyun Tan, Zijie Wang.

Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial-to-mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single-cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1-mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin-6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin-mediated mitophagy.

DOI: https://doi.org/10.1111/cpr.13699
Front Pharmacol. 2024 ;15 1420643

Insights into the role of mitophagy in lung cancer: current evidence and perspectives.

Xin Zhang, Dongzhi Yu, Peng Tang, Fengshou Chen.

  Lung cancer, recognized globally as a leading cause of malignancy-associated morbidity and mortality, is marked by its high prevalence and lethality, garnering extensive attention within the medical community. Mitophagy is a critical cellular process that plays a crucial role in regulating metabolism and ensuring quality control within cells. Its relevance to lung cancer has garnered significant attention among researchers and scientists. Mitophagy's involvement in lung cancer encompasses its initiation, progression, metastatic dissemination and treatment. The regulatory landscape of mitophagy is complex, involving numerous signaling proteins and pathways that may exhibit aberrant alterations or mutations within the tumor environment. In the field of treatment, the regulation of mitophagy is considered key to determining cancer chemotherapy, radiation therapy, other treatment options, and drug resistance. Contemporary investigations are directed towards harnessing mitophagy modulators, both inhibitors and activators, in therapeutic strategies, with an emphasis on achieving specificity to minimize collateral damage to healthy cellular populations. Furthermore, molecular constituents and pathways affiliated with mitophagy, serving as potential biomarkers, offer promising avenues for enhancing diagnostic accuracy, prognostic assessment, and prediction of therapeutic responses in lung cancer. Future endeavors will also involve investigating the impact of mitophagy on the composition and function of immune cells within the tumor microenvironment, aiming to enhance our understanding of how mitophagy modulates the immune response to lung cancer. This review aims to comprehensively overview recent advancements about the role of mitophagy in the tumor genesis, progenesis and metastasis, and the impact of mitophagy on the treatment of lung cancer. We also discussed the future research direction of mitophagy in the field of lung cancer.

Keywords:  autophagy; lung cancer; mitophagy; progression and metastasis; treatment; tumorigenesis

DOI:  https://doi.org/10.3389/fphar.2024.1420643
Nat Commun. 2024 Jul 05. 15(1): 5664

GTPBP8 plays a role in mitoribosome formation in human mitochondria.

Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.

Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.

DOI: https://doi.org/10.1038/s41467-024-50011-x
Cell Death Dis. 2024 Jul 02. 15(7): 473

Macrophage migration inhibitory factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury.

Tianlong Li, Jiachen Qu, Chang Hu, Jingjing Pang, Yaoyao Qian, Yiming Li, Zhiyong Peng.

Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein-protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.

DOI: https://doi.org/10.1038/s41419-024-06826-z
J Cell Physiol. 2024 Jun 30.

IGF2 promotes the differentiation of chicken embryonic myoblast by regulating mitochondrial remodeling.

Changbin Zhao, Bowen Hu, Xiaoyin Zeng, Ze Zhang, Wen Luo, Hongmei Li, Xiquan Zhang.

  Skeletal muscle is crucial for animal movement and posture maintenance, and it serves as a significant source of meat in the livestock and poultry industry. The number of muscle fibers differentiated from myoblast in the embryonic stage is one of the factors determining the content of skeletal muscle. Insulin-like growth factor 2 (IGF2), a well-known growth-promoting hormone, is crucial for embryonic and skeletal muscle growth and development. However, the specific molecular mechanism underlying its impact on chicken embryonic myoblast differentiation remains unclear. To elucidate the molecular mechanism by which IGF2 regulates chicken myoblast differentiation, we manipulated IGF2 expression in chicken embryonic myoblast. The results demonstrated that IGF2 was upregulated during chicken skeletal muscle development and myoblast differentiation. On the one hand, we found that IGF2 promotes mitochondrial biogenesis through the PGC1/NRF1/TFAM pathway, thereby enhancing mitochondrial membrane potential, oxidative phosphorylation, and ATP synthesis during myoblast differentiation. This process is mediated by the PI3K/AKT pathway. On the other hand, IGF2 regulates BNIP3-mediated mitophagy, clearing dysfunctional mitochondria. Collectively, our findings confirmed that IGF2 cooperatively regulates mitochondrial biogenesis and mitophagy to remodel the mitochondrial network and enhance mitochondrial function, ultimately promoting myoblast differentiation.

Keywords:  IGF2; mitochondrial biogenesis; mitochondrial function; mitophagy; myoblast differentiation

DOI:  https://doi.org/10.1002/jcp.31351
Cell Death Dis. 2024 Jul 05. 15(7): 484

BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC.

Sikai Wang, Hongxia Cheng, Miaomiao Li, Dongmei Gao, Haoran Wu, Shanshan Zhang, Yilan Huang, Kun Guo.

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.

DOI: https://doi.org/10.1038/s41419-024-06870-9
World J Gastroenterol. 2024 Jun 21. 30(23): 2934-2946

From macroautophagy to mitophagy: Unveiling the hidden role of mitophagy in gastrointestinal disorders.

Duo-Lun Gao, Meng-Ran Lin, Nan Ge, Jin-Tao Guo, Fan Yang, Si-Yu Sun.

  In this editorial, we comment on an article titled "Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases", which was published in a recent issue of the World Journal of Gastroenterology. We focused on the statement that "autophagy is closely related to the digestion, secretion, and regeneration of gastrointestinal cells". With advancing research, autophagy, and particularly the pivotal role of the macroautophagy in maintaining cellular equilibrium and stress response in the gastrointestinal system, has garnered extensive study. However, the significance of mitophagy, a unique selective autophagy pathway with ubiquitin-dependent and independent variants, should not be overlooked. In recent decades, mitophagy has been shown to be closely related to the occurrence and development of gastrointestinal diseases, especially inflammatory bowel disease, gastric cancer, and colorectal cancer. The interplay between mitophagy and mitochondrial quality control is crucial for elucidating disease mechanisms, as well as for the development of novel treatment strategies. Exploring the pathogenesis behind gastrointestinal diseases and providing individualized and efficient treatment for patients are subjects we have been exploring. This article reviews the potential mechanism of mitophagy in gastrointestinal diseases with the hope of providing new ideas for diagnosis and treatment.

Keywords:  Autophagic receptor; Colorectal cancer; Gastric cancer; Gastrointestinal diseases; Inflammatory bowel disease; Mitophagy; Parkin

DOI:  https://doi.org/10.3748/wjg.v30.i23.2934
Mitochondrion. 2024 Jun 27. pii: S1567-7249(24)00084-9. [Epub ahead of print]78 101926

Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.

Nitu L Wankhede, Spandana Rajendra Kopalli, Mrunali D Dhokne, Dishant J Badnag, Pranali A Chandurkar, Shubhada V Mangrulkar, Prajwali V Shende, Brijesh G Taksande, Aman B Upaganlawar, Milind J Umekar, Sushruta Koppula, Mayur B Kale.

  Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Mitochondrial quality control mechanisms; Neurodegenerative disorders; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.mito.2024.101926
FEBS J. 2024 Jun 30.

MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.

Eddie Tam, Khang Nguyen, Hye Kyoung Sung, Gary Sweeney.

  Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron-sulfur domain-containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO-induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p-Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1-dependent mitochondrial fission, mitophagy, FUN14 domain-containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO-induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi-1, prevented IO-induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO-induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission.

Keywords:  insulin resistance; iron overload; mitoNEET; mitochondria; mitochondrial dynamics; reactive oxygen species

DOI:  https://doi.org/10.1111/febs.17214
Brain Behav Immun. 2024 Jun 29. pii: S0889-1591(24)00468-9. [Epub ahead of print]120 513

Commentary on the Article "BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy".

Haiyang Chen, Liuqing Shi, Lu Ren.

DOI: https://doi.org/10.1016/j.bbi.2024.06.028
Cell Biochem Funct. 2024 Jul;42(5): e4085

Calcium (Ca2+) hemostasis, mitochondria, autophagy, and mitophagy contribute to Alzheimer's disease as early moderators.

Fatemeh Hadi, Mahsa Mortaja, Zahra Hadi.

  This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents evidence that the dysregulation of calcium (Ca2+) homeostasis, along with mitochondrial dysfunction and aberrant autophagic processes, may drive the disease's progression during its asymptomatic, preclinical stage. Understanding the intricate molecular interplay that unfolds during this critical period offers a window into identifying novel therapeutic targets, thereby advancing the treatment of neurodegenerative disorders. The review delves into both established and emerging insights into the molecular alterations precipitated by the disruption of Ca2+ balance, setting the stage for cognitive decline and neurodegeneration.

Keywords:  Alzheimer's disease; Ca2+ hemostasis; autophagy; mitochondria; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1002/cbf.4085
Asian J Pharm Sci. 2024 Jun;19(3): 100927

Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition: Harnessing the power of nanotheranostics.

Sagnik Nag, Oishi Mitra, Bhanu Maturi, Simran Preet Kaur, Ankita Saini, Muskan Nama, Soumik Roy, Souvik Samanta, Leena Chacko, Rohan Dutta, Suresh Babu Sayana, Vetriselvan Subramaniyan, Jasvinder Singh Bhatti, Ramesh Kandimalla.

  Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition (DHC), which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies. Despite significant progress in reducing mortality rates from cardiovascular diseases (CVDs), heart failure remains a major cause of increased morbidity among diabetic patients. These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components, and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment. While a variety of conventional diagnostic and therapeutic strategies are available, DHC continues to present a significant challenge. Point-of-care diagnostics, supported by nanobiosensing techniques, offer a promising alternative for these complex scenarios. Although conventional medications have been widely used in DHC patients, they raise several concerns regarding various physiological aspects. Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC, offering a promising approach to deliver drugs beyond the limitations of traditional therapies. This article aims to explore the potential connections between autophagy, mitophagy and DHC, while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.

Keywords:  Autophagy; Diabetes; Diabetic heart condition; Mitophagy; Nanomedicine; Nanotheranostics

DOI:  https://doi.org/10.1016/j.ajps.2024.100927
Arch Biochem Biophys. 2024 Jul 03. pii: S0003-9861(24)00205-4. [Epub ahead of print] 110083

Impaired mitochondrial quality control in fibromyalgia: mechanisms involved in skeletal muscle alteration.

Francesca Inferrera, Ylenia Marino, Ramona D'Amico, Daniela Impellizzeri, Marika Cordaro, Rosalba Siracusa, Enrico Gugliandolo, Roberta Fusco, Salvatore Cuzzocrea, Rosanna Di Paola.

  Fibromyalgia (FMS) is a persistent syndrome marked by widespread musculoskeletal pain and behavioural symptoms. Given the hypothesis linking FMS aetiology to mitochondrial dysfunction and oxidative stress, we examined the biochemical correlation among these factors by studying specific proteins associated with mitochondrial homeostasis in muscle. Additionally, this study investigated the role of Boswellia serrata gum resin extract (BS), known for its various functions, including the potent induction of antioxidant enzymes, in determining protective or reparative mechanisms in the muscle cells. Sprague-Dawley rats were injected with reserpine to induce FMS. These animals exhibited moderate changes in hind limb skeletal muscles, experiencing mobility difficulties. Additionally, there were noteworthy morphological and ultrastructural alterations, along with the expression of myogenin, mitochondrial enzymes and oxidative stress markers in the gastrocnemius muscle. Interestingly, BS demonstrated a reduction in spontaneous motor activity difficulties. Moreover, BS showed a positive impact on musculoskeletal morphostructural aspects, as well as a decrease in oxidative stress and mitochondrial alterations. In particular, BS restored the mRNA expression of citrate synthase and cytochrome-c oxidase subunit II and the activity of electron transfer chain complexes. BS also influenced mitochondrial biogenesis, upregulating PGC-1α expression and the related transcription factors (Nrf1, Tfam, Nrf2, FOXO3a, SIRT3, GCLC, NQO1, SOD2 and GPx4), oxidative stress (lipid peroxidation, GSH levels and GSH-Px activity) and mitochondrial dynamics and function (Mnf2 expression and CoQ10 levels). Overall, this study underlined the key role of the mitochondrial alteration in FMS and that BS had a very high antioxidant effect in these organelles and also in the cells.

Keywords:  mitochondrial alterations; musculoskeletal morphostructural alteration; oxidative stress

DOI:  https://doi.org/10.1016/j.abb.2024.110083
Nat Struct Mol Biol. 2024 Jul 01.

Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.

Julian R Braxton, Hao Shao, Eric Tse, Jason E Gestwicki, Daniel R Southworth.

The mitochondrial chaperonin, mitochondrial heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in the mitochondrial matrix, assisted by its co-chaperone mtHsp10. Despite its essential role in mitochondrial proteostasis, structural insights into how this chaperonin progresses through its ATP-dependent client folding cycle are not clear. Here, we determined cryo-EM structures of a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified in three distinct states, revealing interactions with the mtHsp60 apical domains and C termini that coordinate client positioning in the folding chamber. We further identify an asymmetric arrangement of the apical domains in the ATP state, in which an alternating up/down configuration positions interaction surfaces for simultaneous recruitment of mtHsp10 and client retention. Client is then fully encapsulated in mtHsp60-10, revealing prominent contacts at two discrete sites that potentially support maturation. These results identify distinct roles for the apical domains in coordinating client capture and progression through the chaperone cycle, supporting a conserved mechanism of group I chaperonin function.

DOI: https://doi.org/10.1038/s41594-024-01352-0
J Biol Chem. 2024 Jun 29. pii: S0021-9258(24)02020-9. [Epub ahead of print] 107519

Importance of conserved hydrophobic pocket region in yeast mitoribosomal mL44 protein for mitotranslation and transcript preference.

Jodie M Box, Margo E Higgins, Rosemary A Stuart.

The mitochondrial ribosome (mitoribosome) is responsible for the synthesis of key oxidative phosphorylation subunits encoded by the mitochondrial genome. Defects in mitoribosomal function therefore can have serious consequences for the bioenergetic capacity of the cell. Mutation of the conserved mitoribosomal mL44 protein has been directly linked to childhood cardiomyopathy and progressive neurophysiology issues. To further explore the functional significance of the mL44 protein in supporting mitochondrial protein synthesis we have performed a mutagenesis study of the yeast mL44 homolog, the MrpL3/mL44 protein. We specifically investigated the conserved hydrophobic pocket region of the MrpL3/mL44 protein, where the known disease-related residue in the human mL44 protein (L156R) is located. While our findings identify a number of residues in this region critical for MrpL3/mL44's ability to support the assembly of translationally active mitoribosomes, the introduction of the disease-related mutation into the equivalent position in the yeast protein (residue A186) was found not have a major impact on function. The human and yeast mL44 proteins share many similarities in sequence and structure, however results presented here indicate that these two proteins have diverged somewhat in evolution. Finally, we observed that mutation of the MrpL3/mL44 does not impact the translation of all mitochondrial encoded proteins equally, suggesting the mitochondrial translation system may exhibit a transcript hierarchy and prioritization.

DOI: https://doi.org/10.1016/j.jbc.2024.107519