Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration

Andrew C. Kent, Khairat Bahgat Youssef El Baradie, Mark W. Hamrick

Research output: Contribution to journalReview articlepeer-review

Abstract

The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.

Original languageEnglish (US)
Article number6626484
JournalOxidative medicine and cellular longevity
Volume2021
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Cell Biology

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