What Is Mitochondrial Dysfunction? – The Hallmarks Of Ageing Series

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In this series of articles, we discuss the nine ‘common denominators’ of the ageing process – the hallmarks of ageing. What exactly they are, how they change during ageing, and how we might be able reverse them in the future? Hopefully, by the end of this series, you will have a wider understanding of what actually makes us age.

What Is Mitochondrial Dysfunction?

Mitochondria are tiny structures that exist inside each cell in the human body. They are a wonder of evolution, once independent organisms that are now permanent and vital residents within our cells. They generate power needed for our cells to function, much like a generator producing electricity to power a building. The mitochondrion is rightly known as the cell’s “powerhouse”, converting nutrients from the food we eat into energy that can be used by the cell (in the form of a molecule called ATP). Mitochondria are unusual organelles in that they possesses their own DNA, known as mitochondrial DNA (mtDNA). mtDNA is found within each mitochondrion, separate from the nuclear DNA found within the nucleus of each cell. mtDNA is responsible for creating a limited number of proteins specifically required for mitochondrial energy production.

When a mitochondrion gets damaged, its ability to power the cell is impaired. The main cause of this damage is due to substances produced within the mitochondria, termed free radicals, which are natural byproducts of energy production in the mitochondria. You may recall them from the genomic instability article. Free radicals are highly reactive, tending to damage proteins and DNA. Since the mitochondria produce free radicals as part of their regular functioning, their DNA and proteins are particularly exposed to this kind of damage. As this damage accumulates, the mitochondria become less effective at producing energy (ATP), leading to a state called mitochondrial dysfunction. This article explains mitochondrial dysfunction in greater detail.

An introduction to mitochondrial dysfunction by the American Aging Association

How Are Ageing And Mitochondrial Dysfunction Linked?

Mitochondria are producing a low level of free radicals all of the time. Since mitochondrial DNA is stored within the mitochondria, it is particularly exposed to this source of damage, and is thought to mutate roughly 10 times faster than nuclear DNA. Cellular levels of antioxidants and free radical-scavengers that protect against this damage also decline with age. Consequently, an increasing proportion of the mitochondria within our cells become dysfunctional as we age, meaning that they do not produce ATP as efficiently as they should. These dysfunctional mitochondria are supposed to be destroyed by the cell in a recycling process called autophagy (also called mitophagy where mitochondria specifically are concerned). However, this process becomes disrupted with age (see loss of proteostasis). Consequently, entire cells can eventually be ‘taken over’ by dysfunctional mitochondria.

One way in which mitochondrial dysfunction may contribute to ageing and its diseases is through inefficient ATP production. ATP is an essential fuel for cells of all types. It provides the energy necessary for muscles to contract, for neurons to send electrical impulses, and for cells to control the concentration of ions inside their membranes. It is suggested that a deficit of energy may be responsible for some aspects of ageing, particularly in tissues that demand a lot of energy like muscle. ATP is also required for processes that remove toxic proteins such as amyloid, thought to play a role in many age-associated diseases including Alzheimer’s.

Mitochondria are important to the cell in more ways than merely producing energy. Products of mitochondrial metabolism act as signalling molecules that influence a wide range of cellular processes including apoptosis (cell suicide), autophagy (the disposal of damaged cell components) inflammation and glucose metabolism. These processes may all be disrupted by mitochondrial dysfunction. The accumulation of dysfunctional mitochondria also depletes an essential molecule called nicotinamide adenine dinucleotide (NAD). NAD is necessary for the production of ATP, but is also used in many processes that are vital to the cell such as the repair of damaged DNA, the recycling of damaged cell components, and the growth and division of existing mitochondria.

How Can Mitochondrial Dysfunction Be Measured?

Various approaches can be used to measure mitochondrial function in isolated mitochondria and cells. Simply studying the microscopic appearance of mitochondria can be an indication of mitochondrial function, as can the expression of certain genes involved in mitochondrial growth and division. The rate of energy production itself can be studied by measuring the electrical potential across the mitochondrial membrane, which is necessary to power the proteins that are used to produce ATP. Levels of oxidative stress, the result of free radical production, can also serve as a measure of mitochondrial function. However, culturing cells in a dish changes the behaviour of their mitochondria, as they are not exposed to the same signals and do not metabolise the same nutrients as when they are within a living organism. Measuring mitochondrial dysfunction within living organisms may therefore be more relevant to human health, though it is also more challenging and less precise.

Changes in patterns of gene expression and protein production may suggest altered mitochondrial function. Since most of the oxygen we breathe is consumed within mitochondria to produce ATP, measuring the rate of oxygen consumption or speed of recovery from exercise may be used as an indicator of mitochondrial function, though this relationship is not straightforward since ATP production may be influenced by other factors such as the supply of nutrients to the mitochondria.

Imaging techniques such as positron emission tomography (PET) allow the uptake of nutrients by cells to be measured directly, providing a dynamic picture of energy use in different locations. Nutrient uptake is indicative of mitochondrial energy production, but again, the relationship is not straightforward.

How Might Mitochondrial Dysfunction Be Fixed?

One of the main underlying causes of mitochondrial dysfunction appears to be mutations in the mtDNA. As discussed in the first article of this series, such mutations are challenging to reverse, but this does not mean that mitochondrial dysfunction could not be prevented or even reversed through other means. For example, drugs could be used to protect mitochondria against damage from free radicals and promote the destruction and replacement of damaged mitochondria. One drug that has already been mentioned in this series, metformin, can protect mitochondria against oxidative damage. Another compound with therapeutic potential is coenzyme Q10, an enzyme that can protect against mitochondrial damage, improve ATP production and promote growth of new mitochondria.

There is also interest in therapies targeting NAD levels and the enzymes that depend on NAD, namely sirtuins. In response to NAD levels, sirtuins regulate the cell’s metabolism in response to the availability of nutrients, and also regulate the expression of genes in response to damage. Compounds that boost NAD (such as vitamin B3) or that activate sirtuins (such as resveratrol and pterostilbene) appear to have some anti-ageing properties in animals. However, human data remains sparse, and the health benefits of boosting NAD and sirtuin activity in humans remains controversial.

One of the most ambitious methods for tackling mitochondrial dysfunction is to insert backup copies of mitochondrial DNA into the cell nuclei, which is a much safer environment than the interior of the mitochondria. This is not an unrealistic goal, since during our shared evolution, almost all of the thousand or so mitochondrial genes have already been driven out of the mitochondria and into the cell nucleus by evolutionary pressure. The SENS research foundation’s mitoSENS project has already succeeded in making backups of two mitochondrial genes function correctly in human cell nuclei. The next step is to study the effects of these backups in mouse models.