Every cell contains hundreds of mitochondria, the evolved descendants of what were once symbiotic bacteria. Much of the original mitochondrial DNA has migrated into the cell nucleus, and mitochondria have become essential components of the cell, subject to quality control mechanisms that recycle malfunctioning and worn mitochondria, as is the case for other organelles. Nonetheless, mitochondria still behave very much like bacteria. They divide to make up their numbers, fuse together, and readily exchange component structures and proteins. Mitochondria are vital to cell function in a number of ways, the most important of which is their production of the chemical energy store molecule adenosine triphosphate (ATP). Cells rely upon ATP to power the chemistry of life.
With advancing age, mitochondria throughout the body change in size, structure, and function. They generate a greater amount of damaging oxidative molecules in the course of making ATP, and the production of ATP declines. Quality control is impaired and malfunctioning mitochondria accumulate. Some are made to malfunction as a result of damage to the remnant mitochondrial genomes, other dysfunction appears to be a consequence of age-related changes in the level of expression of critical mitochondrial genes found in the cell nucleus. This mitochondrial dysfunction also generates continual inflammatory signaling via maladaptive interactions between damaged mitochondria and their debris and defense mechanisms in the cell.
In today’s open access paper, the authors propose a quite different view of mitochondrial dysfunction. In their hypothesis, there is a decline in the ability of mitochondria to appropriately adapt to the lower demand for ATP in aged tissues. Without appropriate regulation, excess material for the production of ATP keeps on arriving to clutter up the environment, giving rise to the observed side-effect of increased production of oxidative molecules and other issues. It is an interesting point of view, and seems worthy of an attempt to produce supporting experimental evidence.
Frailty is a clinical syndrome of reduced physiological reserve and disproportionate vulnerability to stressors in older adults. The dominant cellular model attributes frailty to mitochondrial bioenergetic insufficiency, supported by convergent evidence of reduced mitochondrial respiratory capacity, lower mitochondrial DNA (mtDNA) content and altered substrate metabolism in frail individuals across multiple tissues. Several reproducible features of the phenotype are nevertheless difficult to reconcile with a strict bioenergetic deficit interpretation. Particularly consequential for the present proposal is that cellular energetic demand itself declines progressively with age. Sedentariness, reduced muscle mass, anabolic resistance and the involution of brown adipose tissue together reduce cellular ATP turnover, shifting the balance between substrate input and demand toward chronic excess of input relative to consumption.
Building on these considerations, we propose a complementary framework in which frailty originates in energetic congestion, a state in which a chronically reduced demand allows substrate to persist beyond utilisation, while substrate input itself remains broadly preserved, with the consequence that the regulatory coupling between substrate availability and cellular need is progressively lost. Mitochondrial dysfunction in this view is real but reframed in its directionality. The mitochondrion is not failing because fuel is scarce. It is failing because the fall in demand-driven ATP turnover is not matched by a comparable reduction in substrate delivery, so that oxidative flux is uncoupled from cellular need, while mitochondrial adaptability, the capacity of the organelle to coordinate output with fluctuating energetic demand, is progressively impaired.
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