Mitochondrial dysfunction, proteotoxicity, and aging: causes or effects, and the possible impact of NAD+-controlled protein glycation.
Aging is frequently characterized by the accumulation of altered proteins and dysfunctional mitochondria. This review discusses possible causes of these effects, their interdependence and the impact of energy metabolism on proteostasis, especially formation and elimination of altered proteins. It is suggested NAD+ to some degree regulates formation of aberrant proteins and generation of oxygen free-radicals and reactive oxygen species (ROS), because when NAD+ is limiting, glycolytic triose phosphates spontaneously decompose into methylglyoxal (MG), a highly deleterious glycating agent and ROS inducer. That NAD+ has stimulatory effects on stress protein expression and autophagy, while mitochondria regenerate NAD+ from NADH, further integrates energy metabolism into proteostasis. It is suggested that, as altered proteins can deleteriously interact with mitochondria, changes in synthesis, or elimination, of cytosolic error-proteins will affect mitochondrial activity. It is also suggested that functional mitochondria are essentially antiaging agents, while their dysfunction or inactivity accelerate ROS formation and aging. These proposals may also help explain the oxygen paradox that while ROS may be causal to aging, increased mitochondrial activity (i.e., oxygen utilization) suppresses aging and much associated pathology. Increased synthesis of glutathione, humanin, and mitochondrial chaperone proteins are other additional consequences of increased mitogenesis and which would help ensure proteostasis.
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom. alanandjill@lineone.net
Alan R
AR
Hipkiss
D000375:Aging / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D009243:NAD