By Beatrice Filippi, University of Leeds, UK, & Andrew Philp, University of Birmingham, UK, @andyphilp_lab
Mitochondria, the energy producing bodies within our cells, play a pivotal role in all aspects of body function. Different pathological conditions such as Type 2 Diabetes, cardiovascular disease, neurodegenerative diseases and aging have all been associated to the loss of mitochondrial function.
As such, understanding how mitochondria are regulated in these disease states holds tremendous therapeutic potential for tackling numerous diseases of aging. Over the past two days, scientists from around the world have been discussing current topics in mitochondrial function at The Physiological Society’s sponsored ‘Mitochondria: Form and Function’ meeting in London. The meeting has focused on 4 main topics thought central in the regulation of mitochondrial function; (1) calcium signalling, (2) mitochondrial dynamics, (3) mitophagy, and (4) mitochondrial metabolism. Below is a brief summary of the topics discussed in each symposium.
Calcium and Mitochondria
The mitochondria can take up and release calcium depending on their cellular needs. The calcium in the mitochondria is involved in energy production. Rises in calcium in the cell also activate or inhibit different cellular events. Finally, changes in calcium levels in the mitochondria can trigger cell death. The identification of the molecules that control the mitochondria’s calcium homeostasis (i.e. the levels of calcium inside or outside the mitochondria) has been the focus of the scientific community for the last few years. This will favour the development of more targeted therapies that specifically restore the ability of the mitochondria to regulate calcium homeostasis.
In response to excess or lack of nutrients, mitochondria adapt their functions by changing shape and localization within the cell and increasing or decreasing in number. Fusion causes the formation of bigger and elongated mitochondria and is linked with increased energy generation. For example, insulin increases mitochondria fusion in heart muscle cells to improve mitochondrial membrane potential (the difference in ions on both sides of the membrane), elevate levels of energy in the cell, and oxygen consumption. Mitochondria fission, or separation into smaller parts, is linked with a decrease in energy production in response to energy excess. The adaptation to changes in metabolic environment, meaning energy levels, is controlled by changes in mitochondrial dynamics. Alterations in the fission/fusion mechanisms have been associated to various metabolic diseases like obesity and diabetes and neurodegenerative diseases, like Parkinson and Alzheimer’s.
To maintain healthy and functional mitochondria, mitochondria undergo cyclical periods of synthesis and degradation. The process of mitochondrial degradation is termed mitophagy, and appears to be of specific functional importance in all tissues within the body. Of interest, compared to other aspects of mitochondrial regulation, such as calcium handling and dynamics, very little is known about how mitophagy is regulated and what the physiological signals are that causes mitophagy to begin in cells. One of the main limitations in the field is the ability to measure mitophagy in vivo, meaning in living cells. However, this gap in knowledge appears to have been addressed by the generation of new mouse models in which researchers can visualise when mitophagy is happening in real time. Moving forward, these tools could help shed light on how mitophagy contributes to mitochondrial control in numerous diseases of aging.
Mitochondria are dynamically regulated within our body and highly sensitive to changes in physiological stimuli such as exercise, inactivity and changes in diet. The focus of the final symposium was on two key factors, (1) how exercise changes mitochondrial content (the molecules inside of it) and function in skeletal muscle, and (2) how our diet affects mitochondrial function. It has been known for over 50 years that exercise increases mitochondrial content and the result is an increased oxidative capacity of the muscle (their ability to use oxygen) and greater resistance to fatigue. It also now appears that exercise changes mitochondrial dynamics in skeletal muscle, and alters the organisation of mitochondrial form and function. In contrast, ingestion of high amounts of saturated fats can lead to the development of Type 2 Diabetes, with this process appearing to occur in parallel to a reduction in mitochondrial function. Of note, this negative effect can be inherited in offspring when the mother ingests a high-fat diet, suggesting genetic imprinting, heritable changes in genes, is occurring. Therefore, strategies to maximise the exercise signal(s) or combat the negative effects of saturated fats on mitochondrial function are being explored as frontline approaches to combat numerous diseases of aging.