Toward understanding genomic instability, mitochondrial dysfunction and aging. (8th October 2018)

• Record Type: Journal Article
• Authors: Fakouri, Nima B.; Hou, Yujun; Demarest, Tyler G.; Christiansen, Louise S.; Okur, Mustafa N.; Mohanty, Joy G.; Croteau, Deborah L.; Bohr, Vilhelm A.
• Is Part Of: FEBS journal. Volume 286:Number 6(2019)
• Page Start: 1058
• Page End: 1073
• Publication Date: 2018-10-08
• Subjects: DNA damage -- mitochondria -- mitophagy -- NAD + -- PARP; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14663
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : The biology of aging is an area of intense research, and many questions remain about how and why cell and organismal functions decline over time. In mammalian cells, genomic instability and mitochondrial dysfunction are thought to be among the primary drivers of cellular aging. This review focuses on the interrelationship between genomic instability and mitochondrial dysfunction in mammalian cells and its relevance to age‐related functional decline at the molecular and cellular level. The importance of oxidative stress and key DNA damage response pathways in cellular aging is discussed, with a special focus on poly (ADP‐ribose) polymerase 1, whose persistent activation depletes cellular energy reserves, leading to mitochondrial dysfunction, loss of energy homeostasis, and altered cellular metabolism. Elucidation of the relationship between genomic instability, mitochondrial dysfunction, and the signaling pathways that connect these pathways/processes are keys to the future of research on human aging. An important component of mitochondrial health preservation is mitophagy, and this and other areas that are particularly ripe for future investigation will be discussed. Abstract : Persistence of DNA damage negatively affects mitophagy through NAD + ‐SIRT1–AMPK pathway. DNA damage response activates signaling pathways that negatively affect mitophagy including PARP1 activation followed by NAD + and ATP depletion. A decrease in NAD + and an increase in AMP shifts the mitochondrial balance toward increased mitochondrial activity and decrease in mitophagy. Increased mitochondrial activity is associated with increased ROS production that can damage cellular components and promotes cell death.