The aim of our research is to understand how mitochondrial dysfunction is involved in the aging process and the generation of aging-associated diseases. We are particularly interested in the mechanisms through which mutations in the mitochondrial DNA (mtDNA), which occur in many tissues of all organisms in the normal aging process, lead to the progressive dysfunction of organs.Such mutations accumulate during the normal aging process in many tissues of all organisms.
The classic free-radical-theory of aging (namely the vicious circle of free oxygen radicals from the mitochondrial respiratory chain which cause mtDNA deletions which leads to the generation of more free radicals which raise the mutation load, etc.) has been seriously put into question, maybe even disproved, during the last years. It has been known for a long time that organs like heart, muscle, brain and liver show a mosaic in old individuals, i.e. few cells with a high load of mtDNA-deletions which cause severe mitochondrial dysfunction are embedded in normal tissue. Although it is obvious that in some cases even few damaged cells will severely impact organ function (i.e. the normal conduction of electrical impulses in the heart, the generation of force in the heart and skeletal muscle and the normal function of neuronal networks), experimental models which confirm this assumption are still pending. In other tissues, which do not depend this much on the collaboration of cells, even few cells with damaged mitochondria can cause chronic inflammation processes.
To answer the question if such a tissue mosaic is indeed causally involved in the dysfunction of organs or chronic inflammation during aging, we generated a mouse model which allows to reach an accumulation of mtDNA-deletions and/or depletion in a tissue-specific way. We showed that even very few cardiomyocytes with disturbed mitochondrial function can cause arrhythmia in old mice (Baris et al., Cell Metab 2015; funded by CECAD and DFG Normalverfahren).
Our earlier work brought new insights into the pathophysiological consequences of mtDNA point mutations on the assembly of the respiratory chain. We showed that surprisingly mtDNA-encoded subunits truncated by stop-codons are assembled into big supramolecular complexes which however are degraded quickly by proteases of the inner membrane as a part of the mitochondrial quality control system (Hornig-Do et al., EMBO J 2012; funded by CMMC).
We identified catecholamine metabolism as the driving force behind the accumulation of mtDNA-deletions in dopaminergic neurons, which explains the extremely high mtDNA mutation load in dopaminergic regions of the human brain. This leads to cell loss and M. Parkinson as soon as a threshold of mutated mtDNA-copies is exceeded (Neuhaus et al., Brain 2014; Neuhaus et al., Neuroendocrinol 2015; funded by CMMC). Recently, we have more closely analyzed how mitochondrial dysfunction causes dopaminergic cell death (Ricke et al., J Neurosci 2020; Paß et al., Mol Neurobiol 2020).
We demonstrated that on the other hand the complete absence of the respiratory chain allows normal differentiation of the epidermis (Baris et. al., Stem Cells 2011; funded by DFG Normalverfahren). We thus concluded that epidermal stem cells, and maybe tissue stem cells in general, are independent of mitochondrial ATP-synthesis. This is replaced by a high capacity for aerobic glycolysis, a strategy often observed in tumor cells („Warburg Effect“). In contrast, a partly assembled respiratory chain leads to a severe inflammatory phenotype of the skin (Weiland et al., J Invest Dermatol 2018; funded by SFB 829).
Moreover, we collected evidence that mitochondrial dysfunction is not causally involved in the development of insulin resistance in skeletal muscle (Franko et al., J Mol Med 2012; funded by CECAD) and liver (Franko et al., J Hepatol 2014; Franko et al., Diabetes 2016; Franko et al., Int J Mol Sci 2017; funded by CECAD), like it was postulated by many authors in this field. Though, an intact insulin signal way is needed for the correct content and function of mitochondria in both tissues. We also have shown the mechanism how metformin, the drug most often prescribed against diabetes, stimulates energy turnover and thus slows down the development of obesity and type 2 diabetes (Schommers et al., J Mol Med 2017; funded by CECAD).
Finally, our group was also part of the development of new tools for the investigation of mitochondria, since we developed a method to isolate qualitatively high mitochondria by means of magnetic beads from cells and mouse tissue together with Miltenyi Biotech GmbH in Bergisch Gladbach (Hornig-Do et al., Anal Biochem 2009; funded by CMMC (Franko et al., PLoS One 2014; funded by CECAD).