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Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts

aging electron transport chain complex i 4-phenylbutyrate

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#1 Engadin

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Posted 29 September 2020 - 09:57 PM








P A Y W A L L E D   S O U R C E :   Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease









  •  Aging progressively increases endoplasmic reticulum (ER) stress.
  •  Increased ER stress precedes mitochondrial dysfunction during aging.
  •  Aging leads to the depletion of subunit peptides of complex I.
  •  Intervention to decease ER stress improves mitochondrial function in aged hearts.
  •  Age induced mitochondrial dysfunction in the heart is at least partly reversible.
Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding 24 mo. old mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.
Graphical abstract

Aging increases ER stress that leads to mitochondrial dysfunction with decreased OXPHOS and ATP generation, increased ROS production and a greater likelihood of permeability transition pore (PTP) opening. The dysfunctional mitochondria in turn increase cardiac injury in aged hearts from superimposed cardiac disease. The greater ER stress is indicated by increased expression of ER stress-related genes and proteins including CHOP (C/EBP Homologous Protein) and cleaved ATF6 (Activating transcription factor 6). Aging decreases the content of multiple mitochondrial proteins, especially subunits of electron transport complex I. Treatment of the aged heart with established ER stress and mitochondrial dysfunction with the small molecule chaperone 4-phenylbutyrate (4-PBA) decreased ER stress and restored mitochondrial function. Thus, ER stress is a key mechanism of age-induced mitochondrial dysfunction and can be improved by intervention, providing a new approach to protect the high risk aged heart from subsequent cardiac disease.











1. Introduction

2. Methods
    2.1. Animal model of aging and treatment
    2.2. Isolation of cardiac mitochondria from young and aged hearts
    2.3. Mitochondrial oxidative phosphorylation (OXPHOS) and enzyme activity
    2.4. Calcium retention capacity (CRC) of isolated mitochondria
    2.5. H2O2 generation in cardiac mitochondria
    2.6. ER stress gene array plates and real-time PCR
    2.7. Proteomic analysis
    2.8. Immunoblotting
    2.9. Statistical analysis
3. Results
    3.1. Aging progressively increased ER stress
    3.2. Aging progressively increased ER stress-induced gene expression
    3.3. Aging decreased OXPHOS, especially in IFM
    3.4. Aging increased ROS generation from IFM
    3.5. Aging sensitized to MPTP opening in IFM
    3.6. Aging led to the depletion of mitochondrial proteins
    3.7. Administration of the small molecule chaperone 4-PBA decreased ER stress and improved mitochondrial function in the aged heart
4. Discussion
    4.1. Activation of ER stress genes in the aged heart
    4.2. Alteration of mitochondrial function during aging
    4.3. Alteration of complex I in the aged heart
    4.4. ER stress mechanisms of mitochondrial dysfunction
    4.5. Study limitations
    4.6. Conclusion and biological context







Edited by Engadin, 29 September 2020 - 09:59 PM.

Also tagged with one or more of these keywords: aging, electron transport chain, complex i, 4-phenylbutyrate

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