The Vital Role of Mitochondria in Alzheimer’s Disease and Dementia
I’m a PhD student at King’s College London, and when I’m not sheltering from a global pandemic, I’m scampering between Guy’s and St. Thomas’ hospitals doing my best impression of a scientist. My research attempts to help pinpoint the early warning signs of age-related diseases, which I hope will facilitate prevention of some of the world’s leading causes of death including Alzheimer’s disease and other dementias. To better prevent these diseases, we need to uncover the biological processes that cause ageing in the brain. As with most problems in science there are several theoretical threads we could pull, but I want to persuade you that mitochondria can help explain why our brains, cognition, and mental health worsen as we get old.
What are mitochondria and where did they come from?
If you’re like most people I know, I imagine you will be compelled to shout, ‘the powerhouse of the cell!’ However, the term ‘mitochondria’ was coined in the late 19th century meaning ‘granule thread’, which immediately made me think of gravy granules, although I would be surprised if mitochondria went as well with my Sunday roast. Now look at them. Teeny-weeny party balloons bursting with energy juice. Many biochemists like to refer to the protein molecules that help mitochondria function as machines. Hi-tech devices gradually moulded into sophisticated structures by evolution to perform specific tasks. They rotate with such rapidity that they could tear your limbs clean off (if they were human-sized). Mercifully, they reside in the watery cytoplasm of our cells, churning out the chemical energy that cells need to function, and jacketed in a double membrane to create the cosy conditions for doing this.
Today, it is well-established that the original mitochondrion must have been an early bacterial cell. When it was out for a walk around 2.5 billion years ago, it was carelessly engulfed by a local bully and reduced to a meagre sausage through a series of evolutionary trade-offs. It was then compelled to provide its lunch money (energy) to the local bully in exchange for a quiet existence. As the mitochondrion gave up more of its responsibilities to the bully, it began making copies of itself to increase production despite its diminishing size. Maybe unsurprisingly, this type of strange event was remarkably rare and there is only evidence to prove that this happened successfully three times. Nevertheless, it may prove essential to the development of multicellular life. The extra energy produced by mitochondria maybe allowed cells to support larger, more complex collections of genes, so life could finally evolve beyond its humble beginnings into the ‘endless forms most beautiful’ we see today.
Malfunction in the conveyor belt
Well, how exactly do our mitochondria generate this ‘lunch money’? Within these subcellular factories exists conveyor belts of protein machines that use the products of food digestion and the oxygen we breathe to remove protons from inside the mitochondria (hydrogen atoms that have donated a subatomic particle called an electron). Protons will cascade back into the mitochondria through diffusion (where molecules move from high to low concentration) and the only way for them to enter is through a protein called ATP synthase. This molecular turbine functions like a hydroelectric dam, using the current of protons to rotate, which converts a molecule called adenosine diphosphate into adenosine triphosphate (ATP) by attaching a phosphate group. ATP is like a Pac Man power pellet for proteins and powers most cellular processes.
Generating copious amounts of energy is so vital to life, if stopped, we would be dead in seconds. Mutations in DNA coding for proteins in this conveyor belt (AKA the electron transport chain) are thought to be responsible for several different disorders that are characterised by dysfunction of the mitochondria and a lack of cellular energy. Fortunately, our cells have evolved mechanisms to identify anything troublesome, so they can fix mitochondria if they aren’t working properly, or in extreme circumstances elicit a response where defective cells eat themselves (autophagy) so everything can be replaced.
Mitochondrial dysfunction is bad for the brain
As we age, mutations and damage to the mitochondria accumulate and quality control processes to correct these become less efficient themselves. This is the perfect storm for metabolic mayhem where faulty mitochondria build-up, healthy mitochondria die, and cells are unable to make new ones. Scientists believe these fundamental changes to a cell’s ability to make energy underlies many age-related diseases, particularly of the heart and brain, where cellular energy demands are high. For example, the brain utilises 20% of all our bodily energy. Worryingly, this makes brains susceptible to disorders where neurons die due to mitochondrial dysfunction, and it is no surprise that some of the most common age-related diseases involve gradual degeneration of an energy-starved brain. Furthermore, neurons cannot divide, which evolutionary biologists argue is a useful property because it preserves the experiences and wisdom written into the neural networks of our brain where cells form up to 10,000 connections. However, if a neuron must eat itself in response to mitochondrial dysfunction, then those connections are lost forever with all the memories. Suffice to say, our neurons — a lot like Beyoncé — are irreplaceable.
Cell death, Alzheimer’s disease, and other conditions
Neuronal cell death, or neurodegeneration, characterises an entire group of age-related diseases including Alzheimer’s and Parkinson’s diseases. Alzheimer’s disease involves degeneration of neurons in the cerebral cortex, the newest layer of the brain responsible for attention, memory, thought, perception, and language. It has been shown that a protein found in Alzheimer’s disease called amyloid beta builds-up in the mitochondria and interferes with the conveyor belt, triggering a cascade of events resulting in cell death. On the other hand, Parkinson’s disease is characterised by degeneration in a motor region of the midbrain called the substantia nigra, leading to tremors, rigidity, and difficulty with movement. Current evidence suggests that accumulation of mutations in mitochondrial proteins such as PINK1 can trigger cell death in these instances as well.
Interestingly, men tend to have a higher metabolic rate since testosterone increases muscle mass and muscle has a high energy demand. Also, men are usually larger and consume more food, and this hastens their metabolic rate. This increases the likelihood of mitochondrial dysfunction partly as a result of greater oxidative stress. When making ATP, mitochondria inadvertently create highly reactive oxygen molecules that cause damage. Higher metabolic rates and greater susceptibility to oxidative stress thus puts men at a higher risk for developing disorders such as Parkinson’s disease, which is twice as common in men!
Breathe!
It’s going to be okay. Thankfully, researchers are uncovering mutations and drug targets for treatment. Drugs like rapamycin can increase the clearance of damaged mitochondria and other potential therapies may be able to correct known mutations. Other approaches may involve stimulating cells to create more mitochondria, removing toxic compounds that inhibit or damage mitochondria like highly reactive oxygen molecules, and removing damaged mitochondria. Sadly, as mitochondria become more dysfunctional with time, our chances of experiencing neurodegeneration and cognitive decline increases. And since this happens later in life, there is no selective pressure to correct this apparent evolutionary mistake — thanks a lot Darwin! As a result, we must learn to take good care of these little sausages so that they can continue doing their jobs. Personally, I think understanding mitochondria as ‘powerhouses’ as well as troublemakers of neurodegeneration will embolden us to discover better ways to maintain them, so that we can support our brain function, cognition, and mental health as we grow old.
Header image source: QuantaMagazine