“The Mitochondrial Basis of Aging and Age-Related Disorders“
1. Introduction
Aging is broadly defined as a time-dependent gradual and progressive decline in living organisms’ cellular and organ functions leading to increased vulnerability to chronic diseases and death [1,2]. Nine candidate hallmarks of mammalian aging have recently been identified and classified under three categories i.e., the primary hallmarks (genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis), the antagonistic hallmarks (mitochondrial dysfunction, deregulated nutrient sensing and cellular senescence), and the integrative hallmarks (stem cell exhaustion and altered intercellular communication) [2].
The primary hallmarks are underlying cause of molecular damage during aging, the antagonistic hallmarks exert beneficial or protective effects at low levels but are deleterious to the organism at high levels, and the integrative hallmarks arise when the cellular homeostatic mechanisms fail to compensate for the accumulating damage [2,3]. Importantly, the aging hallmarks interconnect and impinge upon cellular metabolism, thus targeting metabolism may be a promising strategy towards extending human healthspan and lifespan [3].
Mitochondria – istock
Mitochondria are central to regulating cellular metabolism and homeostasis due to their key roles in bioenergetics, generation of reactive oxygen species (ROS), anabolism and catabolism, iron–sulfur cluster and heme biosynthesis, calcium and iron homeostasis, apoptosis and signal transduction [4,5,6,7,8]. These organelles are vital for life, dynamic and reprogram metabolism in response to cellular stress [5,9]. Mitochondrial dysfunction is linked to various aspects of aging including impaired oxidative phosphorylation (OXPHOS) activity, increased oxidative damage, decline in mitochondrial quality control, reduced activity of metabolic enzymes, as well as changes in mitochondrial morphology, dynamics and biogenesis [10,11].
Mitochondrial dysfunction is also implicated in numerous age-related pathologies including neurodegenerative and cardiovascular disorders, diabetes, obesity and cancer [7,8,12,13,14,15,16,17,18]. The maintenance of mitochondrial and cellular homeostasis requires a tight regulation and coordination between generation of new and removal of damaged mitochondria. The damaged or dysfunctional mitochondria are selectively degraded by a mitochondria-specific autophagy clearance process known as mitophagy, whereas new mitochondria are synthesized by mitochondrial biogenesis. An intricate regulatory network balances the mitophagy and mitochondrial biogenesis processes, thus proper coordination of these two opposing processes is critical for aging and longevity [19,20,21].
Dysfunctional or stressed mitochondria generate signals that trigger activation of mitochondrial-to-nuclear, mitochondrial-to-cytosolic, and non-cell-autonomous responses that act to protect against cell death, and restore cellular and metabolic homeostasis [9,22,23].
Here, I will provide a comprehensive overview on the role of mitochondrial DNA (mtDNA) mutations, ROS, oxidative stress, mitochondrial fission, fusion, biogenesis and turnover pathways in aging. Further, I will discuss the emerging evidence that an imbalance between mitochondrial fission and fusion as well as mitochondrial degradation and biogenesis pathways contribute to the pathogenesis of various age-related disorders. Therapeutic strategies that improve mitochondrial dysfunction by targeting mitochondrial dynamics, quality control and stress response-mediated mitohormesis pathways may benefit humans in terms of healthy aging, protection against age-related diseases, and longevity.
2. Mitochondria, Aging and Age-Associated Pathologies
Mitochondria are vital for life as these organelles serve as the powerhouse or energy currency of the eukaryotic cells. Mitochondria generate energy or adenosine triphosphate (ATP) by breakdown of fuel (i.e., glucose and fatty-acids) through a series of…. [to continue reading, click here]
Mitochondria occupy a substantial portion of the cytoplasmic volume of eucaryotic cells, and they have been essential for the evolution of complex animals. Without mitochondria, present-day animal cells would be dependent on anaerobicglycolysis for all of their ATP. When glucose is converted to pyruvate by glycolysis, only a very small fraction of the total free energy potentially available from the glucose is released.
In mitochondria, the metabolism of sugars is completed: the pyruvate is imported into the mitochondrion and oxidized by O2 to CO2 and H2O. This allows 15 times more ATP to be made than that produced by glycolysis alone.
Mitochondria are usually depicted as stiff, elongated cylinders with a diameter of 0.5–1 μm, resembling bacteria. Time-lapse microcinematography of living cells, however, shows that mitochondria are remarkably mobile and plastic organelles, constantly changing their shape (Figure 14-4) and even fusing with one another and then separating again. As they move about in the cytoplasm, they often seem to be associated with…… [to continue reading, click here]
from: Molecular Biology of the Cell. 4th edition. Copy provided by The National Center for Biotechnology Information of the National Library of Medicine, of the Nation Institute of Health of the U.S. Government
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