bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–10–27
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Cyclophilin D plays a critical role in the survival of senescent cells.
  2. Mitochondrial fatty acid oxidation drives senescence.
  3. Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells.
  4. TRANscranial direct current stimulation for FOcal Refractory epilepsy in mitochondrial disease (TRANSFORM): delayed-start, randomised, double-blinded, placebo-controlled study.
  5. Targeted nanopore sequencing using the Flongle device to identify mitochondrial DNA variants.
  6. Glutamine sensing licenses cholesterol synthesis.
  7. Calcitriol in Friedreich Ataxia.
  8. Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.
  9. Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
  10. Mitochondrial non-energetic function and embryonic cardiac development.
  11. Mitochondrial Transfer Via Tunneling Nanotubes Between Mesenchymal Stem Cells and Retinal Pigment Epithelium In Vitro.
  12. Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice.
  13. Mitochondrial Maintenance in Skeletal Muscle.
  14. Cardiac and Renal Transplantation in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Symptoms: Anesthetic Challenges and Considerations.
  15. DNA stores data in bits after epigenetic upgrade.
  16. PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.
  1. EMBO J. 2024 Oct 24.
    Cyclophilin D plays a critical role in the survival of senescent cells.
    Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.
      Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.
    Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering
    DOI:  https://doi.org/10.1038/s44318-024-00259-2
  2. Sci Adv. 2024 Oct 25. 10(43): eado5887
    Mitochondrial fatty acid oxidation drives senescence.
    Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.
      Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
    DOI:  https://doi.org/10.1126/sciadv.ado5887
  3. Dev Growth Differ. 2024 Oct;66(8): 398-413
    Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells.
    Meri Walter-Manucharyan, Melanie Martin, Julia Pfützner, Franz Markert, Gerhard Rödel, Andreas Deussen, Andreas Hermann, Alexander Storch.
      Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8-NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase-γ by 2'-3'-dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism.
    Keywords:  differentiation; gliogenesis; mtDNA; neural stem cells; neurogenesis
    DOI:  https://doi.org/10.1111/dgd.12946
  4. BMC Neurol. 2024 Oct 22. 24(1): 407
    TRANscranial direct current stimulation for FOcal Refractory epilepsy in mitochondrial disease (TRANSFORM): delayed-start, randomised, double-blinded, placebo-controlled study.
    Katrin A Bangel, Albert Z Lim, Alasdair Blain, Yi Shiau Ng, Amy Winder, Joseph Bulmer, Grainne Gorman, Mark Baker, Robert McFarland.
       BACKGROUND: Focal epilepsy is common in children and adults with mitochondrial disease. Seizures are often refractory to pharmacological treatment and, in this patient group, frequently evolve to refractory focal status epilepticus (also known as epilepsia partialis continua). Where this occurs, the long-term prognosis is poor. Transcranial DC stimulation (tDCS) is a promising, non-invasive, adjunctive treatment alternative to common surgical procedures. Limited recruitment of study participants with this rare disease and the ethical challenges of administering a treatment to one group and not another, while maintaining strict methodological rigour can pose challenges to the design of a clinical study.
    METHOD: We designed the first delayed start, double-blinded, sham-controlled study to evaluate the efficacy of tDCS as an adjunctive treatment for focal epilepsy. We will include participants with a genetically confirmed diagnosis of mitochondrial disease with drug-resistant focal epilepsy aged ≥ 2 years, aiming to collect 30 episodes of focal status epilepticus, each treated for a maximum period of 14 days. The early start intervention arm will receive tDCS from day 1. The delayed start intervention arm will receive sham stimulation until crossover on day 3. Our primary endpoint is a greater than 50% reduction from baseline (on day 0) in seizure frequency assessed by 3x daily reporting, accelerometery, and video monitoring. Changes in the underlying epileptogenic focus within the brain related to the tDCS intervention will be assessed by magnetic resonance imaging (MRI) and/or electroencephalography (EEG).
    DISCUSSION: Study results in favour of treatment efficacy would support development of tDCS into a mainstream treatment option for focal epileptic seizures related to mitochondrial disease.
    TRIALS REGISTRATION: ISRCTN: 18,241,112; registered on 16/11/2021.
    Keywords:  Cathodal neuromodulation; DC stimulation; Delayed-start study design; Mitochondrial disease; Mitochondrial epilepsy; Pharmacoresistant epilepsy; Refractory focal seizures; Transcranial direct current stimulation (tDCS)
    DOI:  https://doi.org/10.1186/s12883-024-03907-6
  5. Sci Rep. 2024 Oct 24. 14(1): 25161
    Targeted nanopore sequencing using the Flongle device to identify mitochondrial DNA variants.
    Shintaro Akamatsu, Satomi Mitsuhashi, Kaima Soga, Heisuke Mizukami, Makoto Shiraishi, Martin C Frith, Yoshihisa Yamano.
      Variants in mitochondrial genomes (mtDNA) can cause various neurological and mitochondrial diseases such as mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS). Given the 16 kb length of mtDNA, continuous sequencing is feasible using long-read sequencing (LRS). Herein, we aimed to show a simple and accessible method for comprehensive mtDNA sequencing with potential diagnostic applications for mitochondrial diseases using the compact and affordable LRS flow cell "Flongle." Whole mtDNA amplification (WMA) was performed using genomic DNA samples derived from four patients with mitochondrial diseases, followed by LRS using Flongle. We compared these results to those obtained using Cas9 enrichment. Additionally, the accuracy of heteroplasmy rates was assessed by incorporating mtDNA variants at equimolar levels. Finally, mtDNA from 19 patients with Parkinson's disease (PD) was sequenced using Flongle to identify disease risk-associated variants. mtDNA variants were detected in all four patients with mitochondrial diseases, with results comparable to those obtained from Cas9 enrichment. Heteroplasmy levels were accurately detected (r2 > 0.99) via WMA using Flongle. A reported variant was identified in three patients with PD. In conclusion, Flongle can simplify the traditionally cumbersome and expensive mtDNA sequencing process, offering a streamlined and accessible approach to diagnosing mitochondrial diseases.
    Keywords:  Long-read DNA sequencing; Mitochondrial disease; Targeted sequencing
    DOI:  https://doi.org/10.1038/s41598-024-75749-8
  6. EMBO J. 2024 Oct 21.
    Glutamine sensing licenses cholesterol synthesis.
    Bruna Martins Garcia, Philipp Melchinger, Tania Medeiros, Sebastian Hendrix, Kavan Prabhu, Mauro Corrado, Jenina Kingma, Andrej Gorbatenko, Soni Deshwal, Matteo Veronese, Luca Scorrano, Erika Pearce, Patrick Giavalisco, Noam Zelcer, Lena Pernas.
      The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.
    Keywords:  Cholesterol; HMGCR; MFN2; Nutrient Sensing; SREBP2
    DOI:  https://doi.org/10.1038/s44318-024-00269-0
  7. Mov Disord. 2024 Sep;39(9): 1653-1654
    Calcitriol in Friedreich Ataxia.
    Shana E McCormack, David R Weber, David R Lynch.
      
    DOI:  https://doi.org/10.1002/mds.29970
  8. Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00328-X. [Epub ahead of print]
    Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.
    Rosana-Bristena Ionescu, Alexandra M Nicaise, Julie A Reisz, Eleanor C Williams, Pranathi Prasad, Cory M Willis, Madalena B C Simões-Abade, Linda Sbarro, Monika Dzieciatkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti-Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D'Alessandro, Stefano Pluchino.
      Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.
    Keywords:  cellular senescence; cholesterol metabolism; disease modeling; lipid droplets; multi-omics; multiple sclerosis; neural stem cells; neuroimmunology; neurotoxicity; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.stem.2024.09.014
  9. Nat Cell Biol. 2024 Oct 21.
    Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
    Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont.
      Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.
    DOI:  https://doi.org/10.1038/s41556-024-01527-3
  10. Front Cell Dev Biol. 2024 ;12 1475603
    Mitochondrial non-energetic function and embryonic cardiac development.
    Jingxian Shi, Yuxi Jin, Sha Lin, Xing Li, Donghui Zhang, Jinlin Wu, Yan Qi, Yifei Li.
      The initial contraction of the heart during the embryonic stage necessitates a substantial energy supply, predominantly derived from mitochondrial function. However, during embryonic heart development, mitochondria influence beyond energy supplementation. Increasing evidence suggests that mitochondrial permeability transition pore opening and closing, mitochondrial fusion and fission, mitophagy, reactive oxygen species production, apoptosis regulation, Ca2+ homeostasis, and cellular redox state also play critical roles in early cardiac development. Therefore, this review aims to describe the essential roles of mitochondrial non-energetic function embryonic cardiac development.
    Keywords:  ROS; cardiac development; embryo; mitochondria; non-energetic function
    DOI:  https://doi.org/10.3389/fcell.2024.1475603
  11. J Vis Exp. 2024 Oct 04.
    Mitochondrial Transfer Via Tunneling Nanotubes Between Mesenchymal Stem Cells and Retinal Pigment Epithelium In Vitro.
    Jing Yuan, Zi-Bing Jin.
      Mitochondrial transfer is a normal physiological phenomenon that occurs widely among various types of cells. In the study to date, the most important pathway for mitochondrial transport is through tunneling nanotubes (TNTs). There have been many studies reporting that mesenchymal stem cells (MSCs) can transfer mitochondria to other cells by TNTs. However, few studies have demonstrated the phenomenon of bidirectional mitochondrial transfer. Here, our protocol describes an experimental approach to study the phenomenon of mitochondrial transfer between MSCs and retinal pigment epithelial cells in vitro by two mitochondrial tracing methods. We co-cultured mito-GFP-transfected MSCs with mito-RFP-transfected ARPE19 cells (a retinal pigment epithelial cell line) for 24 h. Then, all cells were stained with phalloidin and imaged by confocal microscopy. We observed mitochondria with green fluorescence in ARPE19 cells and mitochondria with red fluorescence in MSCs, indicating that bidirectional mitochondrial transfer occurs between MSCs and ARPE19 cells. This phenomenon suggests that mitochondrial transport is a normal physiological phenomenon that also occurs between MSCs and ARPE19 cells, and mitochondrial transfer from MSCs to ARPE19 cells occurs much more frequently than vice versa. Our results indicate that MSCs can transfer mitochondria into retinal pigment epithelium, and similarly predict that MSCs can fulfill their therapeutic potential through mitochondrial transport in the retinal pigment epithelium in the future. Additionally, mitochondrial transfer from ARPE19 cells to MSCs remains to be further explored.
    DOI:  https://doi.org/10.3791/66917
  12. J Immunol. 2024 Oct 21. pii: ji2400467. [Epub ahead of print]
    Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice.
    Valeria Garcia-Flores, Zhenjie Liu, Roberto Romero, Roger Pique-Regi, Yi Xu, Derek Miller, Dustyn Levenson, Jose Galaz, Andrew D Winters, Marcelo Farias-Jofre, Jonathan J Panzer, Kevin R Theis, Nardhy Gomez-Lopez.
      Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Most PTB cases involve intra-amniotic inflammation without detectable microorganisms, termed in utero sterile inflammation, for which there is no established treatment. In this study, we propose homeostatic macrophages to prevent PTB and adverse neonatal outcomes caused by in utero sterile inflammation. Single-cell atlases of the maternal-fetal interface revealed that homeostatic maternal macrophages are reduced with human labor. M2 macrophage treatment prevented PTB and reduced adverse neonatal outcomes in mice with in utero sterile inflammation. Specifically, M2 macrophages halted premature labor by suppressing inflammatory responses in the amniotic cavity, including inflammasome activation, and mitigated placental and offspring lung inflammation. Moreover, M2 macrophages boosted gut inflammation in neonates and improved their ability to fight systemic bacterial infections. Our findings show that M2 macrophages are a promising strategy to mitigate PTB and improve neonatal outcomes resulting from in utero sterile inflammation.
    DOI:  https://doi.org/10.4049/jimmunol.2400467
  13. Cold Spring Harb Perspect Biol. 2024 Oct 21. pii: a041514. [Epub ahead of print]
    Mitochondrial Maintenance in Skeletal Muscle.
    Laura M de Smalen, Christoph Handschin.
      Skeletal muscle is one of the tissues with the highest range of variability in metabolic rate, which, to a large extent, is critically dependent on tightly controlled and fine-tuned mitochondrial activity. Besides energy production, other mitochondrial processes, including calcium buffering, generation of heat, redox and reactive oxygen species homeostasis, intermediate metabolism, substrate biosynthesis, and anaplerosis, are essential for proper muscle contractility and performance. It is thus not surprising that adequate mitochondrial function is ensured by a plethora of mechanisms, aimed at balancing mitochondrial biogenesis, proteostasis, dynamics, and degradation. The fine-tuning of such maintenance mechanisms ranges from proper folding or degradation of individual proteins to the elimination of whole organelles, and in extremis, apoptosis of cells. In this review, the present knowledge on these processes in the context of skeletal muscle biology is summarized. Moreover, existing gaps in knowledge are highlighted, alluding to potential future studies and therapeutic implications.
    DOI:  https://doi.org/10.1101/cshperspect.a041514
  14. J Cardiothorac Vasc Anesth. 2024 Oct 01. pii: S1053-0770(24)00765-1. [Epub ahead of print]
    Cardiac and Renal Transplantation in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Symptoms: Anesthetic Challenges and Considerations.
    Erik Anderson, Sudarshan Setty, Mariah Dahmen, Matthew M Townsley, John G Augoustides, Rohesh J Fernando.
      
    Keywords:  MELAS; cardiac surgery; cardiac transplant; congenital; lactic acidosis; mitochondrial encephalopathy; renal transplant; stroke-like symptoms
    DOI:  https://doi.org/10.1053/j.jvca.2024.09.138
  15. Nature. 2024 Oct 23.
    DNA stores data in bits after epigenetic upgrade.
    Heidi Ledford.
      
    Keywords:  Epigenetics; Molecular biology; Nanoscience and technology
    DOI:  https://doi.org/10.1038/d41586-024-03443-w
  16. FEBS J. 2024 Oct 21.
    PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.
    Simona Eleuteri, Bao Wang, Gianni Cutillo, Tracy Shi Zhang Fang, Kai Tao, Yan Qu, Qian Yang, Wenyi Wei, David K Simon.
      Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.
    Keywords:  CMA; Fbxw7; PGC‐1α; Parkinson's disease
    DOI:  https://doi.org/10.1111/febs.17276
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