Mitochondria: More than Just Powerhouses

“Mitochondria are the powerhouses of the cell” may be one of the phrases most familiar to any scientist in biology – highlighting the importance of the numerous and tiny organelles to our survival. Indeed, mitochondria are one of the defining features of all eukaryotic life – enabling energy production at the scale needed to sustain multicellular organisms. But their significance goes far beyond that – with mitochondria implicated in a swath of other vital bodily functions and processes. Latest research shows the importance of mitochondrial health in fighting off COVID, as well as the potential deleterious effects that coronavirus infection can have on them.

Origin and Function

A widely held belief is that mitochondria arose as an endosymbiont within one of our prokaryotic ancestors – resulting in a fusion of organisms necessary to give rise to the eukaryotic diversity of life we are most familiar with. This endosymbiont had, and still has, its own genome – so-called mitochondrial DNA (mtDNA). The majority of the mitochondrial genome experienced reduction  or horizontal transfer to the cellular nucleus, leaving behind only the genes truly necessary for the functions mitochondria must carry out themselves. Primarily, these involve genes responsible for respiration and energy production.

But it would be oversimplifying to say that the role mitochondria play is limited to pumping out Adenosine Triphosphate (ATP). After all, the processes involved in mitochondrial respiration are so closely intertwined with other bodily functions and cellular processes that a multitude of dependencies and effects is unavoidable. For example, mitochondria are able to uncouple oxidative phosphorylation in brown fat tissue so as to produce heat rather than ATP. Additionally, mitochondria play a key role in calcium storage, and downstream signaling pathways reliant on calcium. One of these is cellular apoptosis, a process which mitochondria have long been known to be involved in. Studies in squirrel models have even shown that mitochondria in cone cells play an important role in focusing light in the retina.

Disease Implications

The wide-ranging adaptations mitochondria have made to serve such a cornucopia of roles throughout the body should come as no surprise in light of their own evolutionary origins and the closeness of their relationship with their hosts. Corollary to this, their role in disease physiology should also be expected. Indeed, mitochondria also play a role in regulating the activation, differentiation and survival of immune cells. These can be effected through mitochondrial transcription changes, alterations in the metabolic cycle, as well as signaling to initiate pro-inflammatory responses. The fission and fusion of mitochondria, to adjust to external stresses, can also affect the function of immune cells.

Parkinson’s Disease serves as an illuminative example of disease physiology where mitochondria play a role. Mitophagy, the process through which mitochondria are replaced, is known to be compromised in patients with Parkinson’s Disease. Proteins that are of known significance to Parkinson’s have also been demonstrated to play a role in regulating mitophagy. As mitochondria accumulate mutations in mtDNA due to their natural exposure to agents such as Reactive Oxygen Species (ROS), delicate cellular machinery directs their destruction by sensing their depolarization or overaccumulation of ROS. Failure to sense these changes, or to carry out the elimination of the mitochondria in question, is hypothesized to be one of the main reasons for the rapid degradation seen in the nervous functions of Parkinson’s Disease patients. Neurons are some of the most energy-demanding tissues in the body, and genetic mutations that impair the ability of mitochondria to operate efficiently are likely to become apparent there. 

Much of the mitochondrial impairments seen in Parkinson’s are driven by genetic mutations. But similar physiological disease mechanisms are also seen in patients with long COVID, where muscle fatigue and brain fog are commonly reported symptoms. Studies have already begun investigating the intersection between the two, with an Oxford University-led trial on the effect of therapeutics which can accelerate mitochondrial repair. Studies also show that SARS-CoV-2 also directs its genetic material towards the mitochondria once inside the cell, influencing the production of ROS, mitophagy, iron storage, platelet coagulation and cytokine production. 

Future Directions

These wide-ranging effects show that the mitochondria, while still playing their crucial role as powerhouses of the cell, are much more than simple energy factories. With an evolutionary history closely entwined with ours, there is a growing intersection between their function and the ways it is impacted by disease. Perturbed mitochondrial function can have a plethora of damaging effects – and future investigations would do well to highlight the role mitochondria may play in disease pathophysiology. The role played by mitochondria also offers therapeutic opportunities – mtDNA presents a tempting target for gene editing, although the technology to achieve this is still in its infancy.

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