IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57142-9.html
   My bibliography  Save this article

Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson’s disease models

Author

Listed:
  • Ge Gao

    (Northwestern University Feinberg School of Medicine)

  • Yong Shi

    (Northwestern University Feinberg School of Medicine)

  • Han-Xiang Deng

    (Northwestern University Feinberg School of Medicine)

  • Dimitri Krainc

    (Northwestern University Feinberg School of Medicine)

Abstract

Dysregulation of mitochondrial function has been implicated in Parkinson’s disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson’s disease.

Suggested Citation

  • Ge Gao & Yong Shi & Han-Xiang Deng & Dimitri Krainc, 2025. "Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson’s disease models," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57142-9
    DOI: 10.1038/s41467-025-57142-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57142-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57142-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sebastian Schmidt & Constantin Stautner & Duc Tung Vu & Alexander Heinz & Martin Regensburger & Ozge Karayel & Dietrich Trümbach & Anna Artati & Sabine Kaltenhäuser & Mohamed Zakaria Nassef & Sina Hem, 2023. "A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    2. Ira E. Clark & Mark W. Dodson & Changan Jiang & Joseph H. Cao & Jun R. Huh & Jae Hong Seol & Soon Ji Yoo & Bruce A. Hay & Ming Guo, 2006. "Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin," Nature, Nature, vol. 441(7097), pages 1162-1166, June.
    3. Jeehye Park & Sung Bae Lee & Sungkyu Lee & Yongsung Kim & Saera Song & Sunhong Kim & Eunkyung Bae & Jaeseob Kim & Minho Shong & Jin-Man Kim & Jongkyeong Chung, 2006. "Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin," Nature, Nature, vol. 441(7097), pages 1157-1161, June.
    4. Soojin Kim & Yvette C. Wong & Fanding Gao & Dimitri Krainc, 2021. "Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Sonja Kriks & Jae-Won Shim & Jinghua Piao & Yosif M. Ganat & Dustin R. Wakeman & Zhong Xie & Luis Carrillo-Reid & Gordon Auyeung & Chris Antonacci & Amanda Buch & Lichuan Yang & M. Flint Beal & D. Jam, 2011. "Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease," Nature, Nature, vol. 480(7378), pages 547-551, December.
    6. Hongrui Meng & Chikara Yamashita & Kahori Shiba-Fukushima & Tsuyoshi Inoshita & Manabu Funayama & Shigeto Sato & Tomohisa Hatta & Tohru Natsume & Masataka Umitsu & Junichi Takagi & Yuzuru Imai & Nobut, 2017. "Loss of Parkinson’s disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c," Nature Communications, Nature, vol. 8(1), pages 1-18, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Foozhan Tahmasebinia & Yinglu Tang & Rushi Tang & Yi Zhang & Will Bonderer & Maisa Oliveira & Bretton Laboret & Songjie Chen & Ruiqi Jian & Lihua Jiang & Michael Snyder & Chun-Hong Chen & Yawei Shen &, 2025. "The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    2. Yunpeng Huang & Zhihui Wan & Yinglu Tang & Junxuan Xu & Bretton Laboret & Sree Nallamothu & Chenyu Yang & Boxiang Liu & Rongze Olivia Lu & Bingwei Lu & Juan Feng & Jing Cao & Susan Hayflick & Zhihao W, 2022. "Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Vanitha Nithianandam & Hassan Bukhari & Matthew J. Leventhal & Rachel A. Battaglia & Xianjun Dong & Ernest Fraenkel & Mel B. Feany, 2023. "Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Huan Yang & Caroline Sibilla & Raymond Liu & Jina Yun & Bruce A. Hay & Craig Blackstone & David C. Chan & Robert J. Harvey & Ming Guo, 2022. "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Kimberly C. Paul & Richard C. Krolewski & Edinson Lucumi Moreno & Jack Blank & Kristina M. Holton & Tim Ahfeldt & Melissa Furlong & Yu Yu & Myles Cockburn & Laura K. Thompson & Alexander Kreymerman & , 2023. "A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Federico Miozzo & Eva P. Valencia-Alarcón & Luca Stickley & Michaëla Majcin Dorcikova & Francesco Petrelli & Damla Tas & Nicolas Loncle & Irina Nikonenko & Peter Bou Dib & Emi Nagoshi, 2022. "Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Jenny Zhe Liao & Hyung-lok Chung & Claire Shih & Kenneth Kin Lam Wong & Debdeep Dutta & Zelha Nil & Catherine Grace Burns & Oguz Kanca & Ye-Jin Park & Zhongyuan Zuo & Paul C. Marcogliese & Katherine S, 2024. "Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    8. Katelyn C. Cook & Elene Tsopurashvili & Jason M. Needham & Sunnie R. Thompson & Ileana M. Cristea, 2022. "Restructured membrane contacts rewire organelles for human cytomegalovirus infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Zoë P. Van Acker & Anika Perdok & Ruben Hellemans & Katherine North & Inge Vorsters & Cedric Cappel & Jonas Dehairs & Johannes V. Swinnen & Ragna Sannerud & Marine Bretou & Markus Damme & Wim Annaert, 2023. "Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    10. Willayat Y. Wani & Friederike Zunke & Nandkishore R. Belur & Joseph R. Mazzulli, 2024. "The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson’s disease patient iPSC derived midbrain neurons," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Gustavo Morrone Parfitt & Elena Coccia & Camille Goldman & Kristen Whitney & Ricardo Reyes & Lily Sarrafha & Ki Hong Nam & Soha Sohail & Drew R. Jones & John F. Crary & Alban Ordureau & Joel Blanchard, 2024. "Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Pawel Lisowski & Selene Lickfett & Agnieszka Rybak-Wolf & Carmen Menacho & Stephanie Le & Tancredi Massimo Pentimalli & Sofia Notopoulou & Werner Dykstra & Daniel Oehler & Sandra López-Calcerrada & Ba, 2024. "Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    13. Wei Jiang & Qing Li & Ruofei Zhang & Jianru Li & Qianyu Lin & Jingyun Li & Xinyao Zhou & Xiyun Yan & Kelong Fan, 2023. "Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Hideyuki Takahashi & Sanaea Bhagwagar & Sarah H. Nies & Hongping Ye & Xianlin Han & Marius T. Chiasseu & Guilin Wang & Ian R. Mackenzie & Stephen M. Strittmatter, 2024. "Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    15. Marc Thilo Figge & Andreas S Reichert & Michael Meyer-Hermann & Heinz D Osiewacz, 2012. "Deceleration of Fusion–Fission Cycles Improves Mitochondrial Quality Control during Aging," PLOS Computational Biology, Public Library of Science, vol. 8(6), pages 1-18, June.
    16. Juliane Tschuck & Vidya Padmanabhan Nair & Ana Galhoz & Carole Zaratiegui & Hin-Man Tai & Gabriele Ciceri & Ina Rothenaigner & Jason Tchieu & Brent R. Stockwell & Lorenz Studer & Daphne S. Cabianca & , 2024. "Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    17. A. de Rus Jacquet & M. Alpaugh & H. L. Denis & J. L. Tancredi & M. Boutin & J. Decaestecker & C. Beauparlant & L. Herrmann & M. Saint-Pierre & M. Parent & A. Droit & S. Breton & F. Cicchetti, 2023. "The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    18. Flavia Giamogante & Lucia Barazzuol & Francesca Maiorca & Elena Poggio & Alessandra Esposito & Anna Masato & Gennaro Napolitano & Alessio Vagnoni & Tito Calì & Marisa Brini, 2024. "A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    19. Zhanna Alekseenko & José M. Dias & Andrew F. Adler & Mariya Kozhevnikova & Josina Anna Lunteren & Sara Nolbrant & Ashwini Jeggari & Svitlana Vasylovska & Takashi Yoshitake & Jan Kehr & Marie Carlén & , 2022. "Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    20. Su Jin Ham & Heesuk Yoo & Daihn Woo & Da Hyun Lee & Kyu-Sang Park & Jongkyeong Chung, 2023. "PINK1 and Parkin regulate IP3R-mediated ER calcium release," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57142-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.