Research Area: Mitochondrial Plasticity in Ageing and Disease
Aging is defined by a decline in the functional capacity of cells, organs and organisms. Mitochondria are intimately linked to a wide range of processes associated with aging but how perturbations in mitochondrial activities contribute to aging remains ill-defined. Organ failure during aging is accompanied by a decline in the bioenergetic capacity of mitochondria and the accumulation of aberrant mitochondria, raising the possibility that mitochondrial dysfunction causally contributes to aging. The devastating consequences of impaired mitochondrial activities are illustrated by numerous inherited encephalomyopathies that are associated with mutations affecting mitochondrial proteins. Since mitochondria are the primary site of cellular energy production and perform vital biosynthetic functions, mitochondrial research has been focused for decades on oxidative phosphorylation and the biogenesis of the organelle. However, the notion that mitochondria are highly plastic and dynamic organelles that constantly fuse and divide opened up new research avenues, which significantly altered the view on the role of mitochondria for cell function. lt became clear that mitochondria do not represent disparate entities in a cell. Rather, they communicate in many ways with their cellular environment resulting in changes of their proteome and shape in response to physiological demands and stress. Mitochondria thus serve as intracellular signaling platforms and regulators of age-related processes.
Our group studies mechanisms underlying the functional plasticity of mitochondria in age and age-associated diseases. We focus on the role of proteases in mitochondria, which are emerging as central regulators of mitochondrial activities, shaping the mitochondrial proteome in response to physiological demands and modulating mitochondrial signaling. Proteolytic activities decline with age and numerous inherited diseases are associated with mutations in mitochondrial proteases, highlighting their central relevance for the functional integrity of mitochondria.
Combining mause genetic approaches with biochemical and quantitative proteomic and metabolomic approaches, we succeeded to identify key roles cf mitochondrial proteases for the regulation cf mitochondrial dynamics (Ehses et al., J. Ce//. Bio/., 2009; Baker et al., EMBO J., 2014; Anand et al., J. Ce// Bio/., 2014; Wai et al., Science, 2015; Korwitz et al., J. Gell Bio/., 2016; Sprenger et al., EMBO Mol. Med., 2019), apoptosis (Saita et al., Nat. Gell Bio/., 2017), phospholipid trafficking in mitochondria (Osman et al., J. Gell Bio/., 2009; Osman et al., EMBO J., 2010; Connerth et al., Science, 2012; Petting et al., Gell Metab., 2013; Aaltonen et al., J. Gell Bio/., 2016; Miliara et al., Nat. Com. 2019), and cellular calcium signalling (König et al., Mol Gell, 2016). These discoveries revealed new regulatory principles and are of fundamental importance for our understanding of age-related pathologies that are associated with a dysfunction of mitochondria.
The mitochondrial i-AAA protease YME1 L balances fusion and fission of mitochondria by processing of the dynamin-like GTPase OPA1 (Anand et al., J. Gell Bio/., 2014). Lass of YME1 L in adult cardiomyocytes of mice leads to mitochondrial fragmentation, cardiomyocyte death and dilated cardiomyopathy, culminating in heart failure (Wai et al., Science 2015). Although mitochondrial fragmentation occurs upon deletion of Yme1/ also throughout the brain, only specific neurons in the spinal cord degenerate leading to motor deficiencies (Sprenger et al., EMBO Mol. Med., 2019). lt is conceivable that the different metabolic profile of cardiomyocytes and neurons explains the different vulnerability towards mitochondrial fragmentation and the lass of YME1 L. lndeed, our recent data demonstrate that YME1 L is regulated by metabolic cues and broadly reshapes the mitochondrial proteome upon mTORC1 inhibition, by degrading >50 mitochondrial proteins. These findings reveal coupling of mitochondrial shape changes with their metabolic function. The YME1 L-dependent metabolic rewiring of mitochondria is critical for growth of some solid tumors. Moreover, the function of YME1 L appears to be intimately linked to inflammatory responses, which we observe in degenerating areas of the spinal cord lacking YME1L.
These findings raise a number of fundamental questions on the function of YME1 L at the interface between mitochondrial dynamics, metabolism, inflammation and cell death, which we will address in the future: How is YME1 L regulated on the molecular level in response to metabolic cues? How does YME1 L determine the metabolic function of mitochondria? How does YME1 L protect against inflammation and cell death? What explains the selective vulnerability of cells towards loss of YME1 L?
We address these questions using mainly cultured cells and mouse as model systems and a broad spectrum of experimental approaches. We combine biochemical and cell biological approaches, live cell imaging, as well as genome editing techniques with quantitative proteomics and metabolomics by mass spectroscopy.
Standard biochemical and cell biological skills and experience in live cell imaging are desirable.