Posted on 1 April 2021
Let’s go back in time – at least 1.5 billion years. The Earth is a very different place: the continents as we know them have not yet formed, the atmosphere contains only a small amount of oxygen, and while life on Earth exists within the ocean, it will be another 500 million years or so before the first multicellular organisms. It might sound like a pretty boring time, but evolution is about to take a rather exceptional and unexpected turn.
Within the 500 million years prior to this time, cells containing ‘organs’ (organelles) were born. These cells, called eukaryotes, are anaerobic, meaning they don’t require oxygen to operate – in fact, oxygen is toxic to them. At some point, one of these cells engulfs another type of cell: an aerobic (utilising oxygen) prokaryote (a cell lacking organelles) that will evolve to become what we now know as mitochondria. We don’t know how many times this happened, but we do know that the cells involved only survived once, forming a symbiotic relationship with each other. There are various theories as to how this relationship was mutually beneficial. The traditional view is that the aerobic prokaryote was able to detoxify oxygen and produce energy for its host, while residing inside the eukaryote may have provided increased protection and a more nutrient-rich environment.
Regardless of how this happened, it’s fortunate for us that it did, because the resultant mitochondria-bearing cell forms the basis of all complex life today. You’ve probably heard of mitochondria, and you probably know that they are the ‘power plants’ of the cell. But how exactly do they work, and why do they come up so often when discussing the ageing process?
To understand what mitochondria do to provide energy for the cell, and how this goes awry in ageing, we need to introduce two key molecular players. The first is adenosine triphosphate, or ATP. This molecule is the cell’s main fuel. It is composed of adenosine and a sugar molecule called ribose, with a chain of three phosphate molecules attached to it. By breaking off one of the three phosphate molecules, energy can be released and used for a variety of purposes. This produces ADP (adenosine diphosphate) which can be made back into ATP by attaching another phosphate molecule – this is the job of the mitochondria.
Our second key player is NAD, standing for nicotinamide adenine dinucleotide. NAD can carry electrons – the negatively charged subatomic particles that orbit atoms. Through the addition of two electrons and one proton, NAD becomes the electron-bearing NADH. If any of these details are confusing, you don’t necessarily need to pay attention to them – just know that ATP and NADH store energy and electrons respectively, and become ADP and NAD respectively when energy/electrons are released.
With these molecules introduced, let’s take a look at the mitochondria itself and how it produces ATP. Mitochondria have an outer membrane and an inner membrane, and it is within the inner membrane (a space called the matrix) that the mitochondria’s work begins.
In order to get started, the mitochondria needs some fuel to burn, and this fuel comes from our food in the form of various nutrients: fatty acids, amino acids (the building blocks of protein), glucose (sugar) and, under some circumstances, ketone bodies. Once broken down into a form usable by the mitochondria, these fuels are delivered to the matrix, where they are consumed by what is known as the Krebs cycle. The Krebs cycle is a complex series of chemical reactions that produces various products, including carbon dioxide. The product relevant for energy production, however, is electrons, which are picked up by NAD to generate NADH.
The next step is to use the electrons carried in NADH molecules to generate ATP, by reattaching ADP’s missing phosphate group. This takes place not in the matrix, but at the inner of the mitochondria’s two membranes in a process called oxidative phosphorylation (Ox-Phos). NADH releases its electron, becoming NAD+ again, and hands that electron over to a protein called complex I, which sits in the inner mitochondrial membrane. That electron is then passed along through a series of molecular pumps, which use it to move protons out of the matrix and into the space between the mitochondria’s two membranes. Since protons have a positive charge, their presence within the inter-membrane space creates an electric force, driving them back into the matrix through a special molecular channel called ATP synthase. The structure of ATP synthase is an interesting topic by itself – it’s a propeller! As protons pass through its channel, the ‘rotor’ of the ATP synthase protein spins. The mechanical energy of this rotation is then transmitted into the bond between ADP and the phosphate group to produce ATP.
As we age, an increasing proportion of the mitochondria within our cells become dysfunctional – that is to say, they do not produce ATP as efficiently as they should. Why does this happen? Damage to DNA is thought to be one of the main drivers of ageing, but nuclear DNA – the 46 chromosomes in the centre of each cell – is not the only DNA that matters. Since mitochondria were once separate organisms, they still retain a small amount of their own DNA (called mtDNA), which resides within the mitochondrial matrix. This DNA is particularly exposed to sources of damage, because ATP production in the mitochondria creates natural by-products called reactive oxygen species (ROS) – molecules that can steal electrons off other molecules, causing them to break apart. Due to this high exposure to ROS, mitochondrial DNA is thought to mutate roughly 10 times faster than nuclear DNA.
It is theorised that this DNA damage may be an important root cause of mitochondrial dysfunction. If a mitochondrion’s DNA is sufficiently damaged, its ability to produce ATP may be impaired, due to reduced production of one or more of the proteins necessary for Ox-Phos. The number of these dysfunctional mitochondria in each cell increases with age depending on the type of tissue, and entire cells may eventually be ‘taken over’ in this way.
So, do these cells run out of ATP? Not exactly – there are other ways for cells to produce ATP without Ox-Phos. Unfortunately, these alternatives not only produce far less ATP than Ox-Phos, but also require the use of NAD, which picks up electrons to become NADH. This creates a problem – now that Ox-Phos has slowed or stopped, that NADH has nowhere to deposit its electrons to become NAD again. That means that the cell is at risk of running out of NAD. If that happens, the cell will no longer be able to produce ATP and will die.
To avoid this, the cell has to make more NAD somehow, and it does this by taking NADH, removing the electrons that would usually be used for Ox-Phos, and instead dumping them outside the cell. Unfortunately, this process generates reactive oxygen species – the molecules with which this whole problem began.
There are multiple ways in which an increase in dysfunctional mitochondria may contribute to diseases of ageing. One of these may simply be 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. For example, both basal and maximal ATP production in muscle cells declines with age, and may contribute to age related decline in muscle strength (sarcopenia). Neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease are associated with the accumulation of toxic proteins to form amyloid plaques. The removal of these toxic proteins is an energy-intensive process that could also be impaired by mitochondrial dysfunction. This is consistent with observations that areas of the brain with high energy demand (such as the cortex, responsible for around 80% of the brain’s energy consumption) tend to be the most damaged by toxic proteins.
Another central mechanism through which mitochondrial dysfunction may contribute to ageing is through the production of reactive oxygen species. As discussed, the accumulation of faulty mitochondria within a cell can turn that cell into a kind of factory for ROS that can damage itself and its neighbours. This shouldn’t be too big a problem for the body as a whole – ROS are short-lived, and can’t travel very far before reacting with other molecules. However, ROS can generate other, more problematic molecules like oxidised low density lipoprotein (LDL), which plays a central role in atherosclerosis. Furthermore, the damage caused by ROS can lead to the production of inflammatory signalling molecules, which last much longer and are drivers of most if not all age-related diseases.
As discussed, the decline in levels of NAD contributes to defective ATP production and the generation of ROS, however, NAD is needed for more than just the production of energy. NAD 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. Of particular interest are sirtuins – enzymes whose activity depends on NAD, and which regulate the cell’s metabolism in response to the availability of nutrients while also participating in the cell’s response to stress. A decline in sirtuin activity, caused by reduced NAD, could contribute to the reduced ability of aged cells to resist stress.
Finally, it has become increasingly apparent that mitochondria play a much larger role in the cell than that of energy factories. 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. Mitochondrial dysfunction may be instrumental to the alteration of these processes with age, contributing to the development of diseases of ageing.
Mitochondria are a wonder of evolution – a once separate organism that is now a fundamental part of our biology. By understanding the changes that occur in mitochondria during ageing, as well as the full extent of their role within the cell, we may hope to develop treatments that slow or reverse these changes and thus slow the ageing process.
Mitochondrial Dysfunction in Aging and Diseases of Aging: https://dx.doi.org/10.3390%2Fbiology8020048
Skeletal muscle aging and the mitochondria: https://dx.doi.org/10.1016%2Fj.tem.2012.12.003
Mitochondria as signaling organelles: https://doi.org/10.1186/1741-7007-12-34
How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You: https://www.fightaging.org/archives/2006/10/how-age-damaged-mitochondria-cause-your-cells-to-damage-you/
Many Shuttles Allow Movement Across the Mitochondrial Membranes: https://www.ncbi.nlm.nih.gov/books/NBK22470/#:~:text=NADH%20cannot%20simply%20pass%20into,carried%20across%20the%20mitochondrial%20membrane.
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