Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation
Due to the high redox activity of the mitochondrion, this organelle can suffer oxidative stress. To manage energy demands while minimizing redox stress, mitochondrial homeostasis is maintained by the dynamic processes of mitochondrial biogenesis, mitochondrial network dynamics (fusion/fission), and...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-10-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172100197X |
| _version_ | 1818737047704174592 |
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| author | Shannon Chiang Nady Braidy Sanaz Maleki Sean Lal Des R. Richardson Michael L.-H. Huang |
| author_facet | Shannon Chiang Nady Braidy Sanaz Maleki Sean Lal Des R. Richardson Michael L.-H. Huang |
| author_sort | Shannon Chiang |
| collection | DOAJ |
| description | Due to the high redox activity of the mitochondrion, this organelle can suffer oxidative stress. To manage energy demands while minimizing redox stress, mitochondrial homeostasis is maintained by the dynamic processes of mitochondrial biogenesis, mitochondrial network dynamics (fusion/fission), and mitochondrial clearance by mitophagy. Friedreich's ataxia (FA) is a mitochondrial disease resulting in a fatal hypertrophic cardiomyopathy due to the deficiency of the mitochondrial protein, frataxin. Our previous studies identified defective mitochondrial iron metabolism and oxidative stress potentiating cardiac pathology in FA. However, how these factors alter mitochondrial homeostasis remains uncharacterized in FA cardiomyopathy. This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism. |
| first_indexed | 2024-12-18T00:46:50Z |
| format | Article |
| id | doaj.art-f4f7a590afe042cbb00cb3bd867a6c2a |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-18T00:46:50Z |
| publishDate | 2021-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-f4f7a590afe042cbb00cb3bd867a6c2a2022-12-21T21:26:46ZengElsevierRedox Biology2213-23172021-10-0146102038Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulationShannon Chiang0Nady Braidy1Sanaz Maleki2Sean Lal3Des R. Richardson4Michael L.-H. Huang5Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, NSW, 2006, AustraliaCentre for Healthy Brain Ageing, University of New South Wales, NSW, 2052, AustraliaDepartment of Pathology, University of Sydney, NSW, 2006, AustraliaSchool of Medical Sciences, University of Sydney, NSW, 2006, Australia; Division of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, 2050, AustraliaMolecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, NSW, 2006, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Corresponding author. Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia.Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, NSW, 2006, Australia; School of Medical Sciences, University of Sydney, NSW, 2006, Australia; Corresponding author. Department of Pathology, Faculty of Medicine and Health, University of Sydney, Australia.Due to the high redox activity of the mitochondrion, this organelle can suffer oxidative stress. To manage energy demands while minimizing redox stress, mitochondrial homeostasis is maintained by the dynamic processes of mitochondrial biogenesis, mitochondrial network dynamics (fusion/fission), and mitochondrial clearance by mitophagy. Friedreich's ataxia (FA) is a mitochondrial disease resulting in a fatal hypertrophic cardiomyopathy due to the deficiency of the mitochondrial protein, frataxin. Our previous studies identified defective mitochondrial iron metabolism and oxidative stress potentiating cardiac pathology in FA. However, how these factors alter mitochondrial homeostasis remains uncharacterized in FA cardiomyopathy. This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism.http://www.sciencedirect.com/science/article/pii/S221323172100197XIron loadingIronMitochondriaCardiomyopathyMitochondrial homeostasis |
| spellingShingle | Shannon Chiang Nady Braidy Sanaz Maleki Sean Lal Des R. Richardson Michael L.-H. Huang Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation Redox Biology Iron loading Iron Mitochondria Cardiomyopathy Mitochondrial homeostasis |
| title | Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation |
| title_full | Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation |
| title_fullStr | Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation |
| title_full_unstemmed | Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation |
| title_short | Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation |
| title_sort | mechanisms of impaired mitochondrial homeostasis and nad metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation |
| topic | Iron loading Iron Mitochondria Cardiomyopathy Mitochondrial homeostasis |
| url | http://www.sciencedirect.com/science/article/pii/S221323172100197X |
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