Tissue-specific mechanisms of mitochondrial DNA is maintenance
Mitochondria, the power stations of a cell, have their own genome, mitochondrial DNA (mtDNA), which is essential for the healthy function of the body. Various genetic diseases are caused by increasing damage or loss of mitochondrial DNA in body tissues of patients; these diseases are often devastating. For unknown reasons only some tissues, often muscle or brain, are affected, while others do not show any symptom.
Our group investigates how mitochondria function and how mtDNA is maintained and duplicated in different organs such as muscle, liver and brain. We try to explain the differences in these tissues and find the factors that are involved in damage, protection and repair of mitochondrial DNA. Thus we aim to explain how the mtDNA diseases are caused and why only some tissues are affected. In the long run we hope to find means to prevent, treat or alleviate the symptoms of these diseases.
To study mitochondria we mainly work with mammalian cell culture and investigate mitochondrial DNA in mouse tissue using molecular biology and biochemical methods. Our aims are to create a dataset of mitochondrial parameters in different tissues like e.g. skeletal muscle, liver and heart as well as different cell types, e.g. neurons and fibroblasts. On the basis of this knowledge we’ll investigate the effects and outcome of disturbed mtDNA maintenance in these cell types: How is mitochondrial DNA damaged? Is the damage removed or does it accumulate? When does it start to impair cellular function? How does mtDNA repair work? As an important factor influencing tissue specificity, we study the roles of the both well and less known mtDNA maintenance factors in the mentioned processes.
Mitochondrial DNA adaptation to genotoxic stress
Our research aims to decipher how mitochondrial DNA (mtDNA) adapts to stress caused extrinsic or intrinsic facotrs such as reactive oxygen species (ROS). The most important source of ROS are superoxides ❶ emitted by the mitochondrial respiratory complexes (RC). Due to its location close to the RC, mtDNA is thought to be especially susceptible to oxidative damage. Contrary to earlier beliefs, mtDNA does not face the insults naked, but is packaged into nucleoprotein complexes called nucleoids ❷. Any proteins involved in mtDNA maintenance and repair ❸ either reside within, or can be recruited into nucleoids. Besides studying the role of some of these proteins in safeguarding mtDNA integrity, we intend to elucidate how mtDNA maintenance mechanisms also result in observed, sometimes pathological sequence rearrangements ❹. Mitochondrial DNA also seems to have a somewhat unexpected role in preventing cell death, which in heart seems to be an adaptation to protect cardiomyocytes against intensive oxidative stress during long adult lifetime ❺. Besides providing insight into mtDNA maintenance mechanisms, the study helps us to understand the pathological aging processes in the cardiac muscle.
- Pohjoismäki JL & Goffart S (2017). The role of mitochondria in cardiac development and protection (2017). Free Radic Biol Med. May;106:345-354. doi: 10.1016/j.freeradbiomed.2017.02.032.
- Torregrosa-Muñumer , Goffart S, Haikonen JA, Pohjoismäki JL (2015). Low doses of ultraviolet radiation and oxidative damage induce dramatic accumulation of mitochondrial DNA replication intermediates, fork regression, and replication initiation shift. Mol Biol Cell. 2015 Nov 15;26(23):4197-208. doi: 10.1091/mbc.E15-06-0390.