Fight Aging!

The primary function of mitochondria is production of the chemical energy store molecule adenosine triphosphate (ATP) to power cell activity, though mitochondria are also integrated into many core cellular processes. Loss of mitochondrial function is an important determinant of the pace of aging, and mitochondrial dysfunction is characteristic of cells in aged tissues. A cell contains hundreds of mitochondria, these organelles descended from the first ancient symbiotic bacteria to take up residence in what would become the ancestor of all eukaryotes. Mitochondria retain an atrophied bacterial genome, and can replicate like bacteria. They also frequently fuse together and promiscuously pass around component parts. The quality of mitochondria is assured in part by these ongoing dynamics, but more importantly by mitochondrially-targeted autophagy, known as mitophagy, that flags dysfunctional mitochondria for delivery to a lysosome where they are broken down and recycled.

The balance between mitochondrial fission and fusion appears important to mitochondrial function, though there is some debate as to why exactly this is the case. Too many small mitochondria and too many large mitochondria may both be bad, and for different reasons. The second order consequences of changes in the complex regulation of mitochondrial fission and fusion are poorly mapped and understood, especially when it comes to how these changes interact with mitophagy and the capacity to remove dysfunctional mitochondria before they cause harm to the cell. Today's open access paper provides an example of this lack of understanding, as the authors are surprised to note that increasing expression of fission regulators has much the same outcome as increasing expression of fusion regulators. In both cases, mitochondria appear to exhibit dynamics associated with greater fission, and the life span of engineered nematode worms is increased. This is not an intuitive outcome.

Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity

The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease.

In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan.

Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains.

Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.