DNA and Mitochondria in Aging – University of Copenhagen

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Projects in DNA and Mitochondria in Aging

Cells need energy in the form of adenosine triphosphate (ATP) for many essential functions. Mitochondria are the primary site of cellular ATP production. The role of mitochondria, however, goes beyond energy metabolism. Mitochondria play a key role in a range of cellular functions including fatty acid catabolism, calcium homeostasis, apoptosis, cell proliferation, and autophagy. Thus, mitochondrial defects cause diverse and complex diseases. 

Mitochondria contain their own genome (mtDNA). MtDNA is a 16.5 kb circular genome that encodes 22 transfer RNAs, two ribosomal RNAs, and 13 proteins that are all subunits of the oxidative phosphorylation system. Human and animal models have shown that mtDNA integrity is essential for proper cell function and organ development and defects in the pathways responsible for mtDNA maintenance cause a number of severe and phenotypically variable diseases. Moreover, inherited and acquired mutations in mtDNA are implicated in the process of aging and in human diseases. The activities of both mtDNA repair and autophagy (an important quality control mechanism that removes abnormal mitochondria from mitochondrial pool), seem to change with age.

Base excision repair (BER) is the major pathway for repair of oxidative DNA lesions that are frequent events in mtDNA. BER is the prominent DNA repair pathway in mitochondria. Our group has been studying nuclear and mitochondrial DNA repair pathways for many years. We are studying mechanisms that damage mtDNA and processes that repair damaged mtDNA or remove mitochondria that harbour a high level of damaged mtDNA by autophagy as well as how perturbations in these processes cause disease and aging. We are using human and animal tissues in our studies.

Recent studies have established that a failure to repair nuclear DNA damage can disturb metabolic pathways that ultimately lead to mitochondrial dysfunction. Thus, an intricate network of biochemical pathways in which disturbances can lead to mitochondrial dysfunction in aging and disease.  Importantly, these findings have opened the way for new, non-invasive intervention settings to improve mitochondrial function.  

Alzheimer disease (AD) is a complex, severely devastating disorder characterized by amyloid-β (Aβ) deposits and neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau protein in the brain. However, a broad scientific consensus about the key molecular events responsible for the initiation and the progression of AD is presently not available. Proper mitochondrial function is critical for neuronal cells, because of their high energy demand. Recent investigations have implicated high expression of Tau and mitochondrial dysfunction in the pathogenesis of several neurodegenerative disorders including AD. We are following the hypothesis that persistent cellular stress caused by mitochondrial dysfunction is among the key AD initiators. As a marker of AD pathology and a potential substrate for cellular stress induced by mitochondrial dysfunction, Tau lesion molecular pathology (i.e. phosphorylation, oligomerization), are being examined in appropriate human cell lines and tissues from human patients and animal models of AD.