While sitting in your elementary school classroom or making some amorphous jelly mold studded with jelly beans, you may have heard the phrase “mighty mitochondria” from your studies on the cell structures. More than just a catchy alliteration, this phrase accurately describes one of the most fundamental components of the cells that make up our bodies. Mitochondria, often referred to as the “powerhouses of the cell”, were first discovered in 1857 by physiologist Albert von Kolliker, and later coined “bioblasts” (life germs) by Richard Altman in 1886. The organelles were then renamed “mitochondria” by Carl Benda twelve years later.  It wasn’t until more than half a century had passed since their discovery that the function of mitochondria began to be unraveled [1].

Today, “mighty mitochondria” are known to play a critical role in providing energy to the cell, maintaining cellular metabolism, as well as regulating cell survival and death.  These organelles are responsible for converting food molecules and oxygen into adenosine triphosphate (ATP). ATP can then be used to provide energy for the cell [2]. Not surprisingly, because of their central role in the cell, dysfunctions in mitochondria have been linked to numerous diseases. Most recently, defects in mitochondria have been linked to the process of neurodegeneration – the progressive death or loss in function of neurons, the cells that make up our brains and nervous system. Such damage to distinct subsets of neurons is the root cause of diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis (ALS, or Lou Gherig’s disease). Whether mitochondrial impairment causes neurodegeneration in these diseases or is merely a consequence of it remains unclear. However, the evidence that these organelles play a strong role in neurodegeneration is growing [3].

Alzheimer’s, Aggregation, and Mitochondrial Damage

Alzheimer’s disease, the 6th leading cause of death in the United States, is just one example of a neurodegenerative disease being linked to mitochondrial dysfunction. Alzheimer’s is characterized by progressive degeneration of neurons in the cortex and hippocampus, the brain regions known for intellectual capacity and memory storage, respectively. This degeneration results in a range of symptoms including dementia, difficulty in problem solving, and mood disturbances.

Originally, it was believed that abnormal aggregation, or clumping, of a protein called amyloid beta (Aβ) was the cause of Alzheimer’s disease, as brains of Alzheimer’s patients are riddled with damage caused by these accumulated proteins. However, recent studies have shown that symptoms of Alzheimer’s occur well before this damage is visible. Aβ, which is a protein that is normally found in healthy cells, only becomes toxic when it becomes misfolded or abnormal in the cell. It is now thought that these free pre-aggregated abnormal pieces of Aβ protein are the disease trigger; that even before the protein clumps together, the disease has started.

A study done by Dr. ShiDu Yan at Columbia University Medical Center found that these abnormal Aβ molecules could cause damage to the mitochondria and inhibit their transport within the cell – something that’s particularly important in neurons. The structure of the neuron is very unique as they have long projections, called axons, which form connections with other neurons in order to communicate information.  These axons can be as long as one meter (from your brain to the tips of your fingers, for example!), so the transport of mitochondria to the end of the axon is essential to providing energy to maintain healthy neuronal connections, or synapses [5]. Without the ability to maintain synaptic connections, these neurons eventually die off, resulting in disease.

The Role of Reactive Oxygen Species

Another link between mitochondrial dysfunction and neurodegenerative diseases is the overproduction of damaging molecules called reactive oxygen species (ROS). ROS are highly active oxygen derivatives that can cause extreme injury and stress to cell structures, ultimately leading to cell death. While ROS are normally created by mitochondria during ATP production, the cell has protective enzymes to convert ROS to less harmful forms, thereby preventing extensive damage. In cases of high ROS production, however, the cell is unable to defend itself and accumulates these toxic species over time. Overproduction of ROS in neurons is frequently observed in patients with Parkinson’s and Huntington’s disease, as well as ALS.  Additionally, mutations in ROS-converting enzymes are commonly found in patients with familial ALS [3].

Besides being the “cell powerhouses”, mitochondria are even more “mighty” as they are the only structure in the cell other than the nucleus that contains DNA. Mitochondrial DNA is relatively small, encoding only 37 genes compared to the approximately 25,000 genes in the DNA of the nucleus. However, fundamental genes that encode proteins for producing ATP are found in this small group.  Mitochondrial DNA mutations and deletions have been found in both patients and mouse models of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, usually as a result of damage by ROS [6].

Findings such as these in the past 10-15 years have provoked a movement in neurodegenerative disease research towards understanding the role of mitochondria in cell metabolism, vitality, and death in hopes of identifying potential targets for therapeutics. It has become increasingly more evident that the common link among all neurodegenerative diseases is the dysfunction in mitochondria and their consequent inability to provide energy and maintain cell health.  Much research is being devoted to determining the exact mechanisms by which the mitochondria are damaged and induce further destruction. Even still, I think we can all appreciate that mitochondria are far more mighty and critical to our well-being than we ever understood them to be in elementary school.

Kelsey Taylor is a PhD student in the Biological and Biomedical Sciences program at Harvard Medical School.

References

[1] Allen, Anna. “Who Discovered Mitochondria” Who Discovered It. http://www.whodiscoveredit.com/who-discovered-mitochondria.html

[2] http://en.wikipedia.org/wiki/Mitochondrion

[3] Petrozzi, L., Ricci, G., Giglioli, N.J., Siciliano, G., Mancuso, M. 2007. Mitochondria and Neurodegeneration. Bioscience Reports 27, 87-104.

[4] 2011 Alzheimer’s Disease Facts and Figures. Alzheimer’s Association. 2011. http://www.alz.org/downloads/Facts_Figures_2011.pdf

[5] Columbia University Medical Center. “Early role of mitochondria in Alzheimer’s Disease may help explain limitations to current beta amyloid hypothesis.” ScienceDaily, 13 Oct. 2010. http://www.sciencedaily.com/releases/2010/10/101013122557.htm

[6] Yang, J., Weissman, L., Bohr, V., Mattson, M. 2009. Mitochondrial DNA Damage and Repair in Neurodegenerative Disorders. DNA Repair 7, 1110-1120. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442166/

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