Xudong Zhu1, Weiyan Shen2, Ke Yao3, Hu Wang1,2, Bo Liu2, Tangliang Li1, Lijuan Song4, Daojun Diao2, Genxiang Mao5, Ping Huang6, Chengtao Li6, Hongbo Zhang7, Yejun Zou8, Yugang Qiu9, Yuzheng Zhao8, Wengong Wang10, Yi Yang8, Zeping Hu3, Johan Auwerx7, Joseph Loscalzo11, Yong Zhou12, Zhenyu Ju2. 1. From the Institute of Aging Research, Hangzhou Normal University School of Medicine, China (X.Z., H.W., T.L.). 2. Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, China (W.S., H.W., B.L., D.D., Z.J.). 3. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China (K.Y., Z.H.). 4. Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (L.S.). 5. Department of Geriatrics, Zhejiang Provincial Key Lab of Geriatrics, Geriatrics Research Institute of Zhejiang Province, Zhejiang Hospital, Hangzhou, China (G.M.). 6. Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Sciences, Ministry of Justice, China (P.H., C.L.). 7. Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Federale de Lausanne, Switzerland (H.Z., J.A.). 8. Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology (Y. Zou, Y. Zhao, Y.Y.). 9. School of Rehabilitation Medicine, Weifang Medical University, China (Y.Q.). 10. Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, China (W.W.). 11. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.L.). 12. Beijing Sanbo Brain Hospital, Capital Medical University, China (Y. Zhou).
Abstract
RATIONALE: PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy. OBJECTIVE: To determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner. METHODS AND RESULTS: Moderate cardiac-specific PGC1α overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc-/- (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1αOE) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1α knock in in G3 (G3 PGC1αOE) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1αOE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. CONCLUSIONS: Fine-tuning the expression of PGC1α is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.
RATIONALE: PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy. OBJECTIVE: To determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner. METHODS AND RESULTS: Moderate cardiac-specific PGC1α overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc-/- (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1αOE) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1α knock in in G3 (G3 PGC1αOE) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1αOE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. CONCLUSIONS: Fine-tuning the expression of PGC1α is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.
Authors: Yan Zhang; Yi Ba; Chang Liu; Guoxun Sun; Li Ding; Songyuan Gao; Jihui Hao; Zhentao Yu; Junfeng Zhang; Ke Zen; Zhongsheng Tong; Yang Xiang; Chen-Yu Zhang Journal: Cell Res Date: 2007-04 Impact factor: 25.617
Authors: Zoltan Arany; Huamei He; Jiandie Lin; Kirsten Hoyer; Christoph Handschin; Okan Toka; Ferhaan Ahmad; Takashi Matsui; Sherry Chin; Pei-Hsuan Wu; Igor I Rybkin; John M Shelton; Monia Manieri; Saverio Cinti; Frederick J Schoen; Rhonda Bassel-Duby; Anthony Rosenzweig; Joanne S Ingwall; Bruce M Spiegelman Journal: Cell Metab Date: 2005-04 Impact factor: 27.287
Authors: Laurie K Russell; Carolyn M Mansfield; John J Lehman; Attila Kovacs; Michael Courtois; Jeffrey E Saffitz; Denis M Medeiros; Maria L Valencik; John A McDonald; Daniel P Kelly Journal: Circ Res Date: 2004-01-15 Impact factor: 17.367
Authors: Jonas Feilchenfeldt; Marie Anne Bründler; Claudio Soravia; Martin Tötsch; Christoph A Meier Journal: Cancer Lett Date: 2004-01-08 Impact factor: 8.679
Authors: Haobo Li; Margaret H Hastings; James Rhee; Lena E Trager; Jason D Roh; Anthony Rosenzweig Journal: Circ Res Date: 2020-02-13 Impact factor: 17.367
Authors: Helen E Collins; Mariame Selma Kane; Silvio H Litovsky; Victor M Darley-Usmar; Martin E Young; John C Chatham; Jianhua Zhang Journal: Front Aging Date: 2021-05-06