Chapter 6

Mitochondrial Dysfunction

Mitochondria are cellular organelles responsible for producing energy in the form of ATP through oxidative phosphorylation, making them essential for many cellular processes.

They also play a role in signalling pathways, cell differentiation, apoptosis, and inflammation. As mitochondria age, their function can become compromised, leading to a variety of pathologies and diseases, including ageing itself.

Mitochondrial dysfunction can occur due to multiple factors, including the accumulation of mutations in mitochondrial DNA (mtDNA), impaired proteostasis, reduced organelle turnover, changes in mitochondrial dynamics, and altered membrane composition.

These changes compromise the contribution of mitochondria to cellular bioenergetics, increase the production of reactive oxygen species (ROS), and may trigger accidental permeabilization of mitochondrial membranes, leading to inflammation and cell death.

The effects of mitochondrial dysfunction are felt throughout the body, leading to a decline in overall healthspan. Studies have shown that mitochondrial dysfunction is associated with an increased risk of age-related diseases, including neurodegenerative diseases, cardiovascular disease, diabetes, and cancer.

The effects of mitochondrial dysfunction are partly due to the impact of mitochondria on the ageing process. Research has shown that mitochondrial dysfunction accelerates ageing in mammals. Improving mitochondrial function through hormesis, a concept where mild toxic treatments trigger beneficial compensatory responses, may improve healthspan.

Hormetic reactions may trigger a mitochondrial defensive response in the same tissue in which mitochondria are defective and even in distant tissues.

Certain compounds, such as metformin and resveratrol, have been shown to induce mitohormesis, leading to increased healthspan in model organisms. However, there is currently no evidence that challenging mitochondria can increase healthspan or lifespan in humans.

In addition to the above, mitochondrial microproteins have been identified as potential anti-ageing factors that link organellar function to organismal homeostasis.

For example, humans, encoded by mtDNA, and MOTS-c, a mitochondrial-encoded microprotein, decline with age but have been shown to improve metabolic healthspan and reduce systemic inflammation when increased.

Several interventions have been proposed to stimulate mitochondrial function, including L-carnitine supplementation, which has been shown to have positive effects on both pre-frail subjects and elderly men.

Elamipretide, a modified tetrapeptide that targets cardiolipin in the inner mitochondrial membrane, has been shown to bind to the IMM protein adenine-nucleotide translocator-1 to inhibit the mitochondria permeability transition, a particular mechanism leading to MMP, and has positive effects on multiple aging-related phenotypes in mice.

Mitochondrial dysfunction has a profound impact on the ageing process and is associated with an increased risk of age-related diseases.

However, interventions that stimulate mitochondrial function have shown promise in improving healthspan and reducing age-related pathologies.

Next Chapter
Loss of Proteostasis

Proteostasis, or protein homeostasis, is the process by which the cell maintains the correct balance of protein synthesis, folding, and degradation.

This is crucial for maintaining the proper functio…

Loss of Proteostasis