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MRC Mitochondrial Biology Unit


Mitochondria are involved in many different biological processes that impact the functioning of the human cell and, when these processes go wrong cause human disease.

The best-known function is energy conversion, where the energy stored in food molecules is converted to produce the fuel of the cell, called adenosine triphosphate (ATP) in a process called oxidative phosphorylation. Every day the cells of our body need to generate our own body weight in ATP to sustain our energy-requiring processes in the cells. How does this work? Breakdown products of sugars, fats and proteins are imported into mitochondria by transport proteins and they are carefully broken down. In the oxidation part, the electrons are harvested from the broken bonds and are run down the respiratory chain, consisting of complex I, II, III and IV, where they eventually end up on the oxygen we breathe, producing water. The electron transfer events of the respiratory chain (redox reactions) are coupled to proton translocation, meaning that protons are pumped out of the mitochondrion, charging it up. In the phosphorylation part, adenosine diphosphate (ADP), the spent fuel, and phosphate are transported into the mitochondrion. Then, ATP synthase fuses ADP and phosphate to form ATP using a rotary mechanism, after which ATP is exported from the mitochondrion to fuel energy-requiring cellular processes in the cell.

Mitochondria are also central to the metabolism of molecules in the cell, as they are involved in the breakdown and synthesis of many molecules that are needed for the function of the cell. Nearly all of the different components in our food will pass through the mitochondrion one way or another. For instance, they are involved in amino acid metabolism, as they carry out their breakdown, interconversion and synthesis of amino acids, which are needed for the synthesis of proteins. They carry out the degradation of fatty acids, the breakdown products of fat, but also provide the building blocks for the synthesis and storage of fat in our body. They are play a crucial role in the degradation of sugars, which we need for ATP synthesis, as mentioned above, are involved in nucleotide metabolism, which are building blocks for our genetic materials RNA and DNA, and make and use many of the vitamins we need to help us live. All these processes are tightly regulated, so that the mitochondria in different cells and organs across our body will perform different functions when needed. This mitochondrial diversity helps to shape development of our cells and organs in the embryo, and how they perform their specialised functions during adult life. However, this also explains why, when something goes wrong in the mitochondria, not all organs just stop working, and why mitochondria play such an important role in specific diseases like diabetes, heart conditions, stroke, and some types of cancer.

A unique feature of mitochondria is that they have their own genetic material, called mitochondrial DNA. It is derived from the DNA of alpha-proteobacteria, which were parasitic endosymbionts that evolved into mitochondria, as permanent organelles of the cell. Mitochondrial DNA encodes several important subunits of complex I, III and IV, and ATP synthase, and thus mitochondria need to have their own transcription, RNA maturation and translation machineries. Mitochondrial DNA is exclusively inherited from the mother, as only the mitochondria of the egg cell are passed on. Mutations of mitochondrial DNA can impact the functions of the respiratory chain and ATP synthase causing mitochondrial diseases of oxidative phosphorylation.

Mitochondria also play an important role in life and death decisions of the human cell, in a process called apoptosis. This may sound strange, but it is vital for the processes of growth and development of the body. For instance, this process is really important in shaping organs of the human body in development. This process is also important in the process of controlling cell growth. In cancer, tumours start to grow uncontrollably, unchecked by these processes, and thus it is not surprising that mitochondria play a key role in cancer and are seen as targets for anti-cancer drugs. The function of mitochondria is also tightly controlled and checked. When they become dysfunctional, cells clear them in a process called mitophagy, when they are engulfed by the lysosome and destroyed. If this process does not function well, it can lead to neurodegenerative diseases, such as Parkinson's.

Mitochondria are deeply embedded in the human cell and have extensive interactions with other organelles, influencing their processes. For instance, they form extensive contacts with the endoplasmic reticulum, which are crucial for calcium maintenance, for protein and for lipid exchange and other processes. Mitochondria also form highly dynamic networks in the cell, which can break up (fission) and come together again (fusion). These processes allow cells to deal with radical changes in energy demands, to counteract damage, and to allow for division, when the mitochondrial population is divided between two halves of the dividing cell.  

Bonds of molecules usually contain two electrons, but if only one is present they form radicals. Radicals derived from oxygen are particularly dangerous as they can react randomly with DNA, RNA, proteins and lipids, causing major damage. High levels of radical formation can lead damage and to mitochondrial dysfunction, which in turn can lead to disease. Luckily, there are many processes in the cell that limit the amount of free radicals that are being formed. Still, these processes can play major parts in stroke, when damage occurs because oxygen floods back in after circulation has been restored, leading to lasting tissue damage. It is also believed that a life-time of damage caused by radicals leads to ageing. Thus, it is important to study these fundamental processes to prevent disease and to lead a long healthy life.

The MRC-MBU studies the mitochondrion at all levels. The Unit identifies the genetic defects at the population and patient level, studies the effects of the mutations on protein, mitochondrial and cellular functions, analyses how mitochondrial functions affects cellular and organ function, and translates this information into the clinics. We also are involved in identifying new opportunties for applications and translations of our research and in knowldege transfer.