Prof. Dr. Aleksandra Trifunovic

Research Area: Mitochondrial dysfunction in ageing and neurodegeneration

Website: http://www.cecad.uni-koeln.de/research/principal-investigators/prof-dr-aleksandra-trifunovic/

1. Research background:

Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. The mitochondrial oxidative phosphorylation (OXPHOS), which produces the majority of cellular energy in the form of ATP, is controlled by two distinct genomes: the nuclear and the mitochondrial genome (mtDNA). Mutations in mitochondrial genes encoded by either genome could cause mitochondrial disorders, and have emerged as a key factor in a myriad of “common” diseases, including Parkinson’s and Alzheimer’s Disease, Type 2 Diabetes, and are strongly linked to the aging process.

Despite all this, it is surprising that our understanding of the mechanisms governing the mitochondrial gene expression, its reliance on the complex nature of dual genome control and associated pathologies remain superficial, with therapeutic interventions largely unexplored.

Remarkably, mitochondria are now also viewed as main regulators of signal transduction. Within a last few years, multiple mitochondria-centric signaling mechanisms have been proposed, including release of reactive oxygen species and the scaffolding of signaling complexes on the outer mitochondrial membrane. It has also been shown that mitochondrial dysfunction causes induction of stress responses, bolstering the idea that mitochondria communicate their fitness to the rest of the cell. Studies in this area are not only of basic scientific interest, but may also provide new avenues towards treatment of mitochondrial dysfunction in a variety of human diseases and ageing.

2. Research questions addresses by the group:

When mitochondria experience stress or when dysfunction occurs, the organelle sends signals to the cell nucleus, which launches different types of adaptive cell responses. Transcription factors are activated and stimulate the expression of specific sets of genes, whose products enable the cell to adapt to the changes. We aim to further understand these largely unknown mechanisms that play a central role in determining the extent of tissue specific defect arising from the respiratory deficiency. The primary focus of our research is in deciphering the precise signaling cascade of the pathogenic mechanisms leading to mitochondrial diseases and ageing, with the ultimate goal of identifying new therapeutic targets and strategies.

Our group has successfully advanced research approaches that focus on the communication between mitochondria and other parts of the cell. Recently, the group has shown that mitochondrial dysfunction is sensed independently of respiratory chain deficiency, questioning the current view on molecular mechanisms contributing to the development of mitochondrial diseases (Dogan et al 2014 Cell Metabolism). In a different study, we examined the conservation of mitochondrial unfolded protein response (UPRmt) in mammals, as we reported that the pathway for induction of mtUPR differs between

C. elegans and mice (Seiferling et al. 2016, EMBO Rep, Szczepanowska et al. EMBO J 2016). We continue working on this stress signaling pathway in mammals, by further in vivo analyzing different proteins proposed to play an important role. Through our interest in maintenance of mitochondrial proteostasis we focus on analyzing the role of mitochondrial matrix proteases CLPXP and LONP1 and their contribution to stress signaling and development of diseases.

3. Possible projects:

  1. Protein homeostasis inside mitochondria highly relies on chaperones and proteases to maintain proper folding and to remove damaged proteins that might otherwise form cell-toxic aggregates. Beside quality control, mitoproteases also modulate and regulate many essential mitochondrial functions, such as trafficking, processing and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy and apoptosis. Of all mitochondrial proteases, the ones that reside in matrix (ClpXP and LonP1) are by far the least studied, and we just started to uncover first mammalian substrates and understand their specific roles in regulation of mitochondrial, cellular and organismal physiology. This project will combine biochemical and molecular biology approaches with novel animal models to elucidate the mechanisms of CLPP function in different tissues in order to decipher a role of CLPP in the whole body metabolism and aging. The overall goal of this project is to identify novel CLPXP substrates, adapters and regulation mechanisms specific to distinct tissues as an important step for understanding function of mammalian CLPP.
  2. Massive progress have been made over last decade in understanding conserved signaling pathways that regulate organismal aging and metabolism. It became increasingly clear that the signaling circuits implicated in the regulation of longevity have a primary role during development. Amazingly enough, mitochondrial dysfunction only during development of roundworm C. elegans is sufficient to reshape the metabolism and trigger longevity. However, it is not known if this is conserved in higher organisms and the signaling pathways allowing this have to be further defined. Therefore, we intend to understand how mitochondrial dysfunction restricted to development affects the organismal metabolism during postnatal life and aging.

4. Applied methods and model organisms:

The group mainly uses in vivo model systems, specifically the roundworm Caenorhabditis elegans and multiple transgenic mice to tackle specific questions of mitochondrial pathophysiology. Many of the transgenic mice models are developed within the group, most recently using the CRISPR/Cas9 techniques. The group relies mainly on various molecular biology techniques to understand the complex signaling pathways, many of which are specifically developed to understand the mitochondrial physiology. To tackle complex molecular mechanisms of specific processes in details, we often turn to mammalian cell based models and different biochemical approaches.

As one of the main aims is to understand the consequences of energy depletion in cells and the organism as a whole, many different bioenergetic techniques and approaches are established within the lab, and within Collaborative Research Center - SFB1218, the lab provides these expertise to the Cologne research community. These include, in vivo metabolic phenotyping of transgenic mice using indirect calorimetry and detailed analysis of mitochondrial respiratory function using high-resolution respirometry.