Mitochondria are the powerhouses of the cell, producing energy for our cells, enabling our cells to carry out their functions.
Most cells contain hundreds of mitochondria, which generate “energy” in the form of adenosine triphosphate (ATP). This is a small molecule which sticks to proteins and other cell components, changing their structure, activating them or switching them off.
Beyond energy production, mitochondria also play crucial roles in:
- Controlling apoptosis (cell death): when mitochondria are damaged, they release cytochrome c and activate caspases, which eventually kill the cell.
- Calcium homeostasis: mitochondria modulate calcium levels in the cell to maintain proper cellular function.
As a side-effect of their energy production, mitochondria also produce reactive oxygen species (also called “free radicals”), which are small, very reactive molecules which in too high levels can damage cell components.
In Parkinson’s disease, mitochondria start to function less well. This leads to impaired energy production and increased oxidative stress.
These dysfunctions have been implicated in the degeneration of dopaminergic neurons in the substantia nigra, a hallmark of Parkinson’s disease.
What goes wrong with mitochondria in Parkinson’s disease?
3. Defective Mitophagy
“Mitophagy” is the process by which damaged mitochondria are selectively removed to prevent their accumulation (it’s autophagy of mitochondria - learn more about autophagy here).
In Parkinson’s disease, damaged mitochondria are often not properly broken down and recycled, leading to their accumulation in neurons.
In genetic Parkinson’s disease, this can happen due to mutations in genes such as PINK1 and Parkin, which code for proteins that label defective mitochondria for breakdown.
In sporadic Parkinson’s disease (the most common form), it could be that some triggers or specific gene variants impair mitophagy, allowing dysfunctional mitochondria to persist and propagate in neurons.
2. Too much oxidative stress
Dopaminergic neurons are highly metabolically active, relying on substantial energy production to maintain their function.
This means that their mitochondria work very hard, generating large amounts of free radicals, which cause oxidative damage to cell components, and to the mitochondria themselves.
Furthermore, dopamine is a molecule that is very susceptible to oxidation, further compounding this effect.
Too much oxidative stress and damaged mitochondria in neurons can lead to cell death, and eventually to Parkinson’s disease.
3. Environmental Toxins and Mitochondrial Dysfunction
Exposure to environmental toxins such as pesticides or chemicals like rotenone and paraquat has been linked to Parkinson’s disease.
These toxins damage mitochondria (for example, they inhibit complex I activity, an important mitochondrial protein complex), ultimately leading to the degeneration of dopaminergic neurons.
In the early 1980s, a group of drug users in California developed rapid-onset parkinsonism after injecting a synthetic opioid contaminated with MPTP, a mitochondrial toxin. Their symptoms, including tremors, bradykinesia (slowness of movement), rigidity, and postural instability, were strikingly similar to those seen in Parkinson's disease.
Neurological examinations confirmed that these individuals had extensive loss of dopaminergic neurons in the substantia nigra, a hallmark of Parkinson’s disease.
Epidemiological studies suggest that prolonged exposure to pesticides, which can damage mitochondria, also increases Parkinson’s disease risk.
4. Potential genetic causes or risk factors
For genetic Parkinson’s disease (accounting for around 10% of Parkinson’s disease), various genes have been found that lead to Parkinson’s disease and play directly or indirectly a role in mitochondrial function.
Examples are:
- PINK1 and Parkin: Coordinate mitophagy (breaking down of mitochondria) by marking damaged mitochondria for degradation.
- LRRK2 (Leucine-rich repeat kinase 2): Involved in mitochondrial dynamics, recycling, and can increase oxidative stress, which can damage mitochondria.
- DJ-1: Functions as an antioxidant and protects mitochondria from oxidative stress.
- SNCA (alpha-synuclein): Aggregated alpha-synuclein impairs mitochondrial function and increases susceptibility to oxidative damage.
Conclusion
Mitochondria play a pivotal role in the health and survival of neurons. Their dysfunction is an important factor in the development and progression of Parkinson’s disease.
However, it’s still difficult to see what comes first: is mitochondrial dysfunction a primary cause of Parkinson’s disease, or is it more a consequence of other things that go wrong in neurons (e.g. accumulation of specific proteins like alpha-synuclein which damage mitochondria, or impaired autophagy, which leads to the accumulation of damaged mitochondria)?
Learn more about the causes of Parkinson’s disease here.
