Piano, Valentina - CAP 32

Uncovering the mechanisms regulating mitochondrial dynamics during cell division

Dr. Valentina Piano

Institute of Human Genetics | CMMC Research Building

CMMC - PI - CAP 32
CMMC - Co-PI - C 18
JRG Leader - Institute for Human Genetics Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Institute of Human Genetics | CMMC Research Building

Robert-Koch-Str. 21

50931 Cologne

Introduction

Our research focuses on uncovering how cells control mitochondrial dynamics, especially during cell division. Abnormal mitochondrial regulation impacts many cellular functions, such as autophagy and cell cycle progression, and is linked to age-related diseases. We aim to unravel the signaling pathways that drive mitochondrial fission and actin-cytoskeleton interaction during mitosis. This work addresses key, unresolved questions about how the cell cycle machinery regulates mitochondrial organization, distribution, and segregation, shedding light on how mitochondrial dysfunction could contribute to disease and aging (Figure 1).

Figure 1

Fig. 1: Despite the redundancy of components and mechanisms that contribute to the accuracy of mitotic progression, the mitotic checkpoint is not flawless and mitotic errors - commonly defined as functional abnormalities of the mitotic structures or abnormal mitotic timing – may occur. Interestingly, in contrast to chromosome segregation and spindle dynamics, our understanding of how the rest of the cellular content, in particular the mitochondrial network, is reorganized and segregated during mitosis is still limited and the impact of defects in these processes on mitotic errors has largely been overlooked (Figure created using BioRender).

Clinical relevance

The overlooked phenotypes arising from defects in mitochondrial dynamics during mitosis have the potential, on one hand, to drive tumorigenesis through chromosome missegregation and genomic instability and, on the other hand, to disrupt tissue homeostasis by inducing mitotic catastrophe followed by cell death. Furthermore, the neglected defects in cell proliferation and genome maintenance may be a contributing factor to the perinatal death and/or exacerbate the abnormal development that are associated to inherited mitochondrial dysfunction. Unravelling the intricate relationship between mitochondrial dynamics and chromosome segregation represents a ground- breaking opportunity to uncover unforeseen roles – that go beyond the conventional focus on metabolism - of altered mitochondrial function in both cancer progression and tissue degeneration and to open up new horizons for therapeutic interventions.

Aim and approach

Our aim is to address these two central questions:

How are fission and transport of mitochondria regulated during mitosis?
What are the consequences on mitotic progression in case of the failure of mitochondrial segregation?

We will pursue a dual approach: i) recreate the protein network responsible for governing the assembly of the mitochondria fission machinery and the connection of mitochondria to actin filaments during mitosis in vitro, to identify essential interactions and post-translational modifications; ii) establish a cellular system to examine the impact of precisely depleting mitochondrial fission during mitosis on mitotic progression and chromosome segregation. Through a comparative analysis of the outcomes from these diverse approaches, we aim to pinpoint the specific regulatory step sufficient for these processes to fail and disrupt normal mitotic progression.