There are tree lectures about the mitochondria in my course. Dr. Pinchas Cohen, the Dean of Davis School of Gerontology, talked about the role of mitochondria in disease and pathology.
Mitochondria have essentially three major functions. They are responsible for cellular respiration, integration of apoptotic signals, which means they control cell death, and production of reactive oxygen species (ROS). Mitochondrial function declines with age as a result of accumulated mutations in the mitochondrial DNA. Mitochondrial disfunction is common in diseases, such as diabetes, neurodegenerative pathologies and cancer.
Interestingly, Dr. Cohen mentioned that there were only three Nobel prizes for research in mitochondrial biology. He anticipates that quite soon there will be a Prize awarded to mitochondria research.
Mitochondria are very different in different tissues. They vary in size, numbers, histologically and in proteins they have. Energy production levels also vary quite significantly. This is due to differences in cellular environment in different cell types. Mitochondria adapt to the surrounding situation.
Mitochondrial DNA can be used to track ancestral origins of the population. For example, all Ashkenazi jews, and there are approximately 8 million of them on the planet can be tracked down to 4 Italian women who lived around 2 thousand years ago.
There are numerous diseases associated with mutations in mitochondrial DNA. It is absolutely not clear why so specific phenotypes are associated with given mtDNA mutations. For exapample, the DEAF 1555 mutation is extremely rare (only 50 families in the world) and only affects the inner ear and nothing else. It causes deafness. However a close mutation is more widely spread and causes both deafness and diabetes. It is absolutely not clear why this happens.
The most common mutation is MELAS 3243. It stands for myopathy, encephalopathy, lactic acedosis and stroke-like episodes. The severity of pathology differs significanly in individuals who have this mutation. Some may only have mild metabolic disfunction, but others would have severe diabetes.
ADPD mutations contribute to Alzheimer’s and Parkinson’s diseases. There’s also a whole cluster of mutations responsible for elevated risk of getting prostate cancer. There are mutations responsible for muscle/cardiac/renal and neuro abnormalities and autism-spectrum disorders.
Dr. Cohen believes that upto 90% of healthcare costs can be reduced by diet and exercise. Unfortunately, lifestyle changes are rarely enforceable.
Mitochondrial dysfunction is recognized to be a contributing factor in malignancy. Specifically, it relates to a transition from aerobic to glycolytic metabolism, resistance to mitochondrial apoptosis, accumulation of mitochondrial mutations and increased levels of mitochondrial transcripts of various lengths in certain cancers, in particular from the 16S rRNA.
Diet and excersise significanly improve mitochondrial function. There are also 3 drugs that are PPAR-gamma agonists that improve mitochondrial function. As do drugs like GLP1, insulin and metformin. Of course, it is not a good idea to supplement yourself with insulin, however metformin seems very promising, especially given the recent publication where patients who have diabetes and take metformin have better survival curves than healthy controls.
When UCP-2 protein levels go down, mitochondrial function is impaired, because the glucose/fatty acid metabolism ratio is changed.
A recent paper showed that mitochondria trancriptome is in fact very interesting and further studies may shed light onto the so far unknown mechanisms of mitochondria function regulation. For example, this paper showed differences in the 13 protein expression ranging from organ to organ. There were also sense and anti-sense RNA detected, as well as small RNAs with unclear roles. Apparently there’s much more to the story of mitochondrial genome and its function that we now understand.
There was a paper by Andrew Dillin and his team that posited there are mitokines that are secreted in the brain, but operate in the gut. It is not known though what mitokines are.
Mitochondria do produce small peptides that influence cellular function. Dr. Cohen has discovered a peptide called humanin. Apparently, higher levels of humanin are associated with less Alzheimer’s disease and less cardio vascular disease. IGF1 decreases humanin levels. More research should be done in mitochondria-derived peptides, since it seems that they may play quite important role in aging and disease.
On a side note when talking about diabetes Dr. Cohen mentioned there are only 5 types of diets: reduced amino acid intake (less meat), reduced carbohydrate intake, reduced fats, low calorie diet and intermittant fasting. He believes that it may be a good idea to adjust one’s diet according to the certain disease risks. For example, if a person has elevated cancer risk, then they should consume less amino acids, and those with higher cardiovascular risks may want to stay away from carbs-enriched foods. These are of course speculations. The only diet that was proven to be beneficial in terms of reducing disease risk is the Midetteranean diet.