bims-tofagi 2023-10-22 papers

on Mitophagy

Issue of 2023‒10‒22
seventeen papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Mitophagy in neurodegenerative disease pathogenesis.
A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.
Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage.
Mitophagy in yeast: known unknowns and unknown unknowns.
Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.
Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in platelets.
Zinc Overload Induces Damage to H9c2 Cardiomyocyte Through Mitochondrial Dysfunction and ROS-Mediated Mitophagy.
The interaction between alpha-synuclein and mitochondrial dysfunction in Parkinson's disease.
C-type natriuretic peptide improves maternally aged oocytes quality by inhibiting excessive PINK1/Parkin-mediated mitophagy.
Latest assessment methods for mitochondrial homeostasis in cognitive diseases.
Novel functions of the ER-located Hsp40s DNAJB12 and DNAJB14 on proteins at the outer mitochondrial membrane under stress mediated by CCCP.
Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging.
Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.
Roles of NAD+ in Health and Aging.
Mitophagy-related genes could facilitate the development of septic shock during immune infiltration.
The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson's disease.

Neural Regen Res. 2024 May;19(5): 998-1005

Mitophagy in neurodegenerative disease pathogenesis.

Kan Yang, Yuqing Yan, Anni Yu, Ru Zhang, Yuefang Zhang, Zilong Qiu, Zhengyi Li, Qianlong Zhang, Shihao Wu, Fei Li.

  Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Keywords:  Alzheimer’s disease; PINK1; Parkin; Parkinson’s disease; amyotrophic lateral sclerosis; autophagy; mitochondria; mitophagy; mitophagy receptor

DOI:  https://doi.org/10.4103/1673-5374.385281
Cell Rep. 2023 Oct 17. pii: S2211-1247(23)01272-X. [Epub ahead of print]42(10): 113260

A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.

Christopher S Waters, Sigurd B Angenent, Steven J Altschuler, Lani F Wu.

  Mechanisms that prevent accidental activation of the PINK1/Parkin mitophagy circuit on healthy mitochondria are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria, where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we explore emergent properties of the PINK1/Parkin circuit by quantifying the relationship between mitochondrial PINK1 concentrations and Parkin recruitment dynamics. We find that Parkin is recruited to mitochondria only if PINK1 levels exceed a threshold and then only after a delay that is inversely proportional to PINK1 levels. Furthermore, these two regulatory properties arise from the input-coupled positive feedback topology of the PINK1/Parkin circuit. These results outline an intrinsic mechanism by which the PINK1/Parkin circuit can avoid errant activation on healthy mitochondria.

Keywords:  CP: Molecular biology; PINK1; Parkin; circuit; delay; mathematical model; mitophagy decision; quantitative microscopy; synthetic biology; systems biology; threshold

DOI:  https://doi.org/10.1016/j.celrep.2023.113260
Neural Regen Res. 2024 Apr;19(4): 825-832

Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage.

Jiatong Zhang, Qi Zhu, Jie Wang, Zheng Peng, Zong Zhuang, Chunhua Hang, Wei Li.

  The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow. Mitochondria are directly affected by direct factors such as ischemia, hypoxia, excitotoxicity, and toxicity of free hemoglobin and its degradation products, which trigger mitochondrial dysfunction. Dysfunctional mitochondria release large amounts of reactive oxygen species, inflammatory mediators, and apoptotic proteins that activate apoptotic pathways, further damaging cells. In response to this array of damage, cells have adopted multiple mitochondrial quality control mechanisms through evolution, including mitochondrial protein quality control, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer, to maintain mitochondrial homeostasis under pathological conditions. Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage. This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage, particularly mitochondrial quality control mechanisms. It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission and fusion; mitochondrial quality control; mitophagy; subarachnoid hemorrhage

DOI:  https://doi.org/10.4103/1673-5374.381493
Biochem J. 2023 Oct 31. 480(20): 1639-1657

Mitophagy in yeast: known unknowns and unknown unknowns.

Hagai Abeliovich.

  Mitophagy, the autophagic breakdown of mitochondria, is observed in eukaryotic cells under various different physiological circumstances. These can be broadly categorized into two types: mitophagy related to quality control events and mitophagy induced during developmental transitions. Quality control mitophagy involves the lysosomal or vacuolar degradation of malfunctioning or superfluous mitochondria within lysosomes or vacuoles, and this is thought to serve as a vital maintenance function in respiring eukaryotic cells. It plays a crucial role in maintaining physiological balance, and its disruption has been associated with the progression of late-onset diseases. Developmentally induced mitophagy has been reported in the differentiation of metazoan tissues which undergo metabolic shifts upon developmental transitions, such as in the differentiation of red blood cells and muscle cells. Although the mechanistic studies of mitophagy in mammalian cells were initiated after the initial mechanistic findings in Saccharomyces cerevisiae, our current understanding of the physiological role of mitophagy in yeast remains more limited, despite the presence of better-defined assays and tools. In this review, I present my perspective on our present knowledge of mitophagy in yeast, focusing on physiological and mechanistic aspects. I aim to focus on areas where our understanding is still incomplete, such as the role of mitochondrial dynamics and the phenomenon of protein-level selectivity.

Keywords:   Saccharomyces cerevisiae ; autophagy; mitophagy

DOI:  https://doi.org/10.1042/BCJ20230279
Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291

Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.

Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.

  Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.

Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2023.113291
Appl Physiol Nutr Metab. 2023 Oct 18.

High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.

James Tincknell, Benjamin Kugler, Haley Spicuzza, Nicolas Berger, Huimin Yan, Tongjian You, Kai Zou.

Mitochondrial quality control processes are essential in governing mitochondrial integrity and function. The purpose of the study was to examine the effects of 10 weeks of HIIT on the regulatory protein machinery of skeletal muscle mitochondrial quality control and whole-body glucose homeostasis in diet-induced obese mice. Male C57BL/6 mice were assigned to low-fat diet (LFD) or high-fat diet (HFD) group. After 10 weeks, HFD-fed mice were divided into sedentary and HIIT (HFD+HIIT) groups for another 10 weeks (n=9/group). Graded exercise test, glucose and insulin tolerance tests, mitochondrial respiration and protein markers of mitochondrial quality control processes were determined. HFD-fed mice exhibited lower ADP-stimulated mitochondrial respiration (P<0.05). However, ten weeks of HIIT prevented this impairment (P < 0.05).. Importantly, the ratio of Drp1(Ser616) over Drp1(Ser637) phosphorylation, an indicator of mitochondrial fission, was significantly higher in HFD-fed mice (P<0.05), but such increase was attenuated in HFD-HIIT compared to HFD (-35.7%, P < 0.05). Regarding autophagy, skeletal muscle p62 content was lower in HFD group than LFD group (-35.1%, P < 0.05), however, such reduction was disappeared in HFD+HIIT group. In addition, LC3B II/I ratio was higher in HFD than LFD group (15.5%, P < 0.05) but was ameliorated in HFD+HIIT group (-29.9%, P < 0.05). Overall, our study demonstrated that 10 weeks of HIIT was effective in improving skeletal muscle mitochondrial respiration and the regulatory protein machinery of mitochondrial quality control in diet-induced obese mice through the alterations of mitochondrial fission protein Drp1 phosphorylations and p62/LC3B-mediated regulatory machinery of autophagy.

DOI: https://doi.org/10.1139/apnm-2023-0286
FASEB J. 2023 Nov;37(11): e23239

Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in platelets.

Pan Pan, Jie Chen, Fei Xie, Yinghua Guo, Xudong Liu, Dong Zhang, Lixin Xie, Longxiang Su.

  Platelets are highly involved in inflammation and organ injury under pathological conditions. The mitophagy in platelets may restrict hyperactivation of the inflammasome and relieve acute kidney injury (AKI). Cecal ligation puncture (CLP)/LPS-induced AKI Triggering receptor expressed on myeloid cells (TREM-1)-knockout mice models were established. Additionally, septic patients with AKI were also included. TREM-1 expression in platelets and inflammasome activation were examined. Platelet transfer assays were performed to investigate the contribution of platelet TREM-1 to renal injury. Mitophagy was evaluated in the context of inflammation. BNIP3L/Nix knockout mice were used to examine the relationship between platelet mitophagy and inflammatory activation. The results showed that the level of TREM-1 was increased and the platelet inflammasome was hyperactivated in CLP mice and septic patients, and TREM-1 activated platelet inflammasomes. TREM-1 deletion significantly abrogated hyperactivation of the platelet inflammasome and dramatically reduced AKI, whereas ablation of the mitophagy receptor BNIP3L/Nix induced the accumulation of damaged mitochondria and hyperactivation of platelet inflammasomes in CLP mice. BNIP3L/Nix controlled platelet inflammasome activation, and an amplification loop of platelet inflammasome activation and dysfunctional mitochondria controlled sepsis-related AKI. Therefore, targeting TREM-1 and NLRP3/BNIP3L in platelets may represent a novel therapeutic strategy for treating septic AKI.

Keywords:  BNIP3L/Nix; NLRP3 inflammasome; TREM-1; autophagy; mitochondrion; platelet

DOI:  https://doi.org/10.1096/fj.202202144RRR
Cardiovasc Toxicol. 2023 Dec;23(11-12): 388-405

Zinc Overload Induces Damage to H9c2 Cardiomyocyte Through Mitochondrial Dysfunction and ROS-Mediated Mitophagy.

Ying Yang, Pei Wang, Jiabao Guo, Tingting Ma, Youcheng Hu, Luyao Huang, Bohan Xing, Yonggui He, Jinkun Xi.

  Zinc homeostasis is essential for maintaining redox balance, cell proliferation, and apoptosis. However, excessive zinc exposure is toxic and leads to mitochondrial dysfunction. In this study, we established a zinc overload model by treating rat cardiomyocyte H9c2 cells with Zn2+ at different concentrations. Our results showed that zinc overload increased LDH and reactive oxygen species (ROS) levels, leading to cell death, mitochondrial membrane potential decrease and impaired mitochondrial function and dynamics. Furthermore, zinc overload activated the PINK1/Parkin signaling pathway and induced mitochondrial autophagy via ROS, while NAC inhibited mitophagy and weakened the activation of PINK1/Parkin pathway, thereby preserving mitochondrial biogenesis. In addition, our data also showed that Mfn2 deletion increased ROS production and exacerbated cytotoxicity induced by zinc overload. Our results therefore suggest that Zn2+-induced ROS generation causes mitochondrial autophagy and mitochondrial dysfunction, damaging H9c2 cardiomyocytes. Additionally, Mfn2 may play a key role in zinc ion-mediated endoplasmic reticulum and mitochondrial interactions. Our results provide a new perspective on zinc-induced toxicology.

Keywords:  H9c2; Mitofusin-2; Mitophagy; Reactive oxygen species; Zinc overload

DOI:  https://doi.org/10.1007/s12012-023-09811-8
Biophys Chem. 2023 Oct 10. pii: S0301-4622(23)00173-4. [Epub ahead of print]303 107122

The interaction between alpha-synuclein and mitochondrial dysfunction in Parkinson's disease.

Hong-Yan Li, De-Shui Liu, Ying-Bo Zhang, Hua Rong, Xiao-Jie Zhang.

  Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with the hallmark of abnormal aggregates of alpha-synuclein (α-syn) in Lewy bodies (LBs) and Lewy neurites (LNs). Currently, pathogenic α-syn and mitochondrial dysfunction have been considered as prominent roles that give impetus to the PD onset. This review describes the α-syn pathology and mitochondrial alterations in PD, and focuses on how α-syn interacts with multiple aspects of mitochondrial homeostasis in the pathogenesis of PD.

Keywords:  Alpha-synuclein; Mitochondrial dysfunction; Mitochondrial homeostasis; Parkinson's disease

DOI:  https://doi.org/10.1016/j.bpc.2023.107122
Elife. 2023 Oct 20. pii: RP88523. [Epub ahead of print]12

C-type natriuretic peptide improves maternally aged oocytes quality by inhibiting excessive PINK1/Parkin-mediated mitophagy.

Hui Zhang, Chan Li, Qingyang Liu, Jingmei Li, Hao Wu, Rui Xu, Yidan Sun, Ming Cheng, Xiaoe Zhao, Menghao Pan, Qiang Wei, Baohua Ma.

  The overall oocyte quality declines with aging, and this effect is strongly associated with a higher reactive oxygen species (ROS) level and the resultant oxidative damage. C-type natriuretic peptide (CNP) is a well-characterized physiological meiotic inhibitor that has been successfully used to improve immature oocyte quality during in vitro maturation. However, the underlying roles of CNP in maternally aged oocytes have not been reported. Here, we found that the age-related reduction in the serum CNP concentration was highly correlated with decreased oocyte quality. Treatment with exogenous CNP promoted follicle growth and ovulation in aged mice and enhanced meiotic competency and fertilization ability. Interestingly, the cytoplasmic maturation of aged oocytes was thoroughly improved by CNP treatment, as assessed by spindle/chromosome morphology and redistribution of organelles (mitochondria, the endoplasmic reticulum, cortical granules, and the Golgi apparatus). CNP treatment also ameliorated DNA damage and apoptosis caused by ROS accumulation in aged oocytes. Importantly, oocyte RNA-seq revealed that the beneficial effect of CNP on aged oocytes was mediated by restoration of mitochondrial oxidative phosphorylation, eliminating excessive mitophagy. CNP reversed the defective phenotypes in aged oocytes by alleviating oxidative damage and suppressing excessive PINK1/Parkin-mediated mitophagy. Mechanistically, CNP functioned as a cAMP/PKA pathway modulator to decrease PINK1 stability and inhibit Parkin recruitment. In summary, our results demonstrated that CNP supplementation constitutes an alternative therapeutic approach for advanced maternal age-related oocyte deterioration and may improve the overall success rates of clinically assisted reproduction in older women.

Keywords:  C-natriuretic peptide; developmental biology; embryonic development; mitophagy; mouse; oocyte; reactive oxygen species; reproductive aging

DOI:  https://doi.org/10.7554/eLife.88523
Neural Regen Res. 2024 Apr;19(4): 754-768

Latest assessment methods for mitochondrial homeostasis in cognitive diseases.

Wei You, Yue Li, Kaixi Liu, Xinning Mi, Yitong Li, Xiangyang Guo, Zhengqian Li.

  Mitochondria play an essential role in neural function, such as supporting normal energy metabolism, regulating reactive oxygen species, buffering physiological calcium loads, and maintaining the balance of morphology, subcellular distribution, and overall health through mitochondrial dynamics. Given the recent technological advances in the assessment of mitochondrial structure and functions, mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, and postoperative cognitive dysfunction. This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences, from the perspectives of energy metabolism, oxidative stress, calcium homeostasis, and mitochondrial dynamics (including fission-fusion, transport, and mitophagy).

Keywords:  calcium homeostasis; cognitive disorders; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial energy metabolism; mitochondrial transport; mitophagy; oxidative stress

DOI:  https://doi.org/10.4103/1673-5374.382222
Mol Cell Biochem. 2023 Oct 18.

Novel functions of the ER-located Hsp40s DNAJB12 and DNAJB14 on proteins at the outer mitochondrial membrane under stress mediated by CCCP.

Pattarawut Sopha, Tirawit Meerod, Bunkuea Chantrathonkul, Nadgrita Phutubtim, Douglas M Cyr, Piyarat Govitrapong.

  The endoplasmic reticulum (ER) membrane provides infrastructure for intracellular signaling, protein degradation, and communication among the ER lumen, cytosol, and nucleus via transmembrane and membrane-associated proteins. Failure to maintain homeostasis at the ER leads to deleterious conditions in humans, such as protein misfolding-related diseases and neurodegeneration. The ER transmembrane heat shock protein 40 (Hsp40) proteins, including DNAJB12 (JB12) and DNAJB14 (JB14), have been studied for their importance in multiple aspects of cellular events, including degradation of misfolded membrane proteins, proteasome-mediated control of proapoptotic Bcl-2 members, and assembly of multimeric ion channels. This study elucidates a novel facet of JB12 and JB14 in that their expression could be regulated in response to stress caused by the presence of ER stressors and the mitochondrial potential uncoupler CCCP. Furthermore, JB14 overexpression could affect the level of PTEN-induced kinase 1 (PINK1) expression under CCCP-mediated stress. Cells with genetic knockout (KO) of DNAJB12 and DNAJB14 exhibited an altered kinetic of phosphorylated Drp1 in response to the stress caused by CCCP treatment. Surprisingly, JB14-KO cells exhibited a prolonged stabilization of PINK1 during chronic exposure to CCCP. Cells depleted with JB12 or JB14 also revealed an increase in the mitochondrial count and branching. Hence, this study indicates the possible novel functions of JB12 and JB14 involving mitochondria in nonstress conditions and under stress caused by CCCP.

Keywords:  ER stress; Hsp40; Intracellular communication; J-protein; Mitochondrial dynamics; Mitochondrial stress response

DOI:  https://doi.org/10.1007/s11010-023-04866-1
Nat Aging. 2023 Oct 16.

Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging.

Yu Zhang, Jie Bai, Zhaokang Cui, Yu Li, Qian Gao, Yilong Miao, Bo Xiong.

Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that the spermidine level was reduced in ovaries of aged mice and that supplementation with spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By microtranscriptomic analysis, we further discovered that spermidine-induced recovery of oocyte quality was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this mechanism of action was conserved in porcine oocytes under oxidative stress. Altogether, our findings suggest that spermidine supplementation could represent a therapeutic strategy to ameliorate oocyte quality and reproductive outcome in cis-gender women and other persons trying to conceive at an advanced age. Future work is needed to test whether this approach can be safely and effectively translated to humans.

DOI: https://doi.org/10.1038/s43587-023-00498-8
Nat Struct Mol Biol. 2023 Oct 19.

Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.

Douglas Adamoski, Marilia Meira Dias, Jose Edwin Neciosup Quesñay, Zhengyi Yang, Ievgeniia Zagoriy, Anna M Steyer, Camila Tanimoto Rodrigues, Alliny Cristiny da Silva Bastos, Bianca Novaes da Silva, Renna Karoline Eloi Costa, Flávia Mayumi Odahara de Abreu, Zeyaul Islam, Alexandre Cassago, Marin Gerard van Heel, Sílvio Roberto Consonni, Simone Mattei, Julia Mahamid, Rodrigo Villares Portugal, Andre Luis Berteli Ambrosio, Sandra Martha Gomes Dias.

Glutaminase (GLS), which deaminates glutamine to form glutamate, is a mitochondrial tetrameric protein complex. Although inorganic phosphate (Pi) is known to promote GLS filamentation and activation, the molecular basis of this mechanism is unknown. Here we aimed to determine the molecular mechanism of Pi-induced mouse GLS filamentation and its impact on mitochondrial physiology. Single-particle cryogenic electron microscopy revealed an allosteric mechanism in which Pi binding at the tetramer interface and the activation loop is coupled to direct nucleophile activation at the active site. The active conformation is prone to enzyme filamentation. Notably, human GLS filaments form inside tubulated mitochondria following glutamine withdrawal, as shown by in situ cryo-electron tomography of cells thinned by cryo-focused ion beam milling. Mitochondria with GLS filaments exhibit increased protection from mitophagy. We reveal roles of filamentous GLS in mitochondrial morphology and recycling.

DOI: https://doi.org/10.1038/s41594-023-01118-0
Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041193. [Epub ahead of print]

Roles of NAD+ in Health and Aging.

Sofie Lautrup, Yujun Hou, Evandro F Fang, Vilhelm A Bohr.

NAD+, the essential metabolite involved in multiple reactions such as the regulation of cellular metabolism, energy production, DNA repair, mitophagy and autophagy, inflammation, and neuronal function, has been the subject of intense research in the field of aging and disease over the last decade. NAD+ levels decline with aging and in some age-related diseases, and reduction in NAD+ affects all the hallmarks of aging. Here, we present an overview of the discovery of NAD+, the cellular pathways of producing and consuming NAD+, and discuss how imbalances in the production rate and cellular request of NAD+ likely contribute to aging and age-related diseases including neurodegeneration. Preclinical studies have revealed great potential for NAD+ precursors in promotion of healthy aging and improvement of neurodegeneration. This has led to the initiation of several clinical trials with NAD+ precursors to treat accelerated aging, age-associated dysfunctions, and diseases including Alzheimer's and Parkinson's. NAD supplementation has great future potential clinically, and these studies will also provide insight into the mechanisms of aging.

DOI: https://doi.org/10.1101/cshperspect.a041193
Medicine (Baltimore). 2023 Oct 20. 102(42): e35154

Mitophagy-related genes could facilitate the development of septic shock during immune infiltration.

Yu-Shen Yang, Wan-Jing Zheng, Chu-Yun Liu, Wei-Can Chen, Wen-Xi Xie, He-Fan He.

Septic shock often occurs following critically low blood pressure in patients with sepsis, and is accompanied by a high death rate. Although mitophagy is associated with infection and immune responses, its role in septic shock remains unknown. This study screened effective mitophagy-related genes (MRGs) for medical practice and depicted immune infiltration situations in patients with septic shock. Gene expression profiles of GSE131761 from the Gene Expression Omnibus database were compiled for differential analysis, weighted gene co-expression network analysis, and immune infiltration analysis, while other GSE series were used as validation datasets. A series of validation methods were used to verify the robustness of hub genes, while a nomogram and prognosis model were established for medical practice. Six genes were screened via combinations of differentially expressed genes, weighted gene co-expression network analysis, and MRGs. From this, 3 hub genes (MAP1LC3B, ULK1, and CDC37) were chosen for subsequent analysis based on different validation methods. Gene set enrichment analysis showed that leukocyte trans-endothelial migration and the p53 signaling pathway were abnormally activated during septic shock. Immune infiltration analysis indicated that the imbalance of neutrophils and CD4 naive T cells was significantly correlated with septic shock progression. A nomogram was generated based on MAP1LC3B, ULK1, and CDC37, as well as age. The stability of our model was confirmed using a calibration plot. Importantly, patients with septic shock with the 3 highly expressed hub genes displayed worse prognosis than did patients without septic shock. MAP1LC3B, ULK1, and CDC37 are considered hub MRGs in the development of septic shock and could represent promising diagnostic and prognostic biomarkers in blood tissue. The validated hub genes and immune infiltration pattern expand our knowledge on MRG functional mechanisms, which provides guidance and direction for the development of septic shock diagnostic and therapeutic markers.

DOI: https://doi.org/10.1097/MD.0000000000035154
Neural Regen Res. 2024 May;19(5): 1150-1155

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson's disease.

Shuanglong Yi, Linfang Wang, Margaret S Ho, Shiping Zhang.

  Parkinson's disease is a progressive neurodegenerative disease characterized by motor deficits, dopaminergic neuron loss, and brain accumulation of α-synuclein aggregates called Lewy bodies. Dysfunction in protein degradation pathways, such as autophagy, has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson's disease. However, it is less well understood how protein aggregates are eliminated in glia, the other cell type in the brain. In the present study, we show that autophagy-related gene 9 (Atg9), the only transmembrane protein in the autophagy machinery, is highly expressed in Drosophila glia from adult brain. Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network, autophagosomes, and lysosomes in glia. Atg9 is persistently in contact with these organelles. Lacking glial atg9 reduces the number of omegasomes and autophagosomes, and impairs autophagic substrate degradation. This suggests that glial Atg9 participates in the early steps of autophagy, and hence the control of autophagic degradation. Importantly, loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons, locomotion deficits, and glial activation. Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson's disease. These results may provide new insights on the underlying mechanism of Parkinson's disease.

Keywords:  Atg9; Parkinson’s disease; autophagy; glia

DOI:  https://doi.org/10.4103/1673-5374.382259