Mitochondrial DNA homeostasis in growing cells

Introduction

Mitochondrial DNA (mtDNA) constitutes a substantial proportion of DNA in eukaryotes, and its regulation is critical not only for mitochondrial function but also for cell survival. However, it is still unclear how mtDNA copy number is maintained during cell proliferation and how mtDNA copy number impacts cell function. Recently, my group showed that in budding yeast, mtDNA copy number is tightly linked to cell volume to maintain constant concentrations, providing an elegant and potentially conserved strategy for mtDNA homeostasis.

Research Question

But how is mtDNA coupled to cell volume? Based on my group’s work, we proposed that nuclear-encoded mtDNA maintenance factors produced in proportion to cell volume limit mtDNA replication and stability. This provides a conceptual mechanism for how cells link mtDNA copy number to total cellular protein content, and opens the door to a quantitative and molecular understanding of mtDNA homeostasis.

Project Goals

With MITOSIZE, I will reveal the molecular basis of this ‘limiting machinery’ mechanism. To test whether the mechanism is conserved across species and to chloroplast DNA, I will use two evolutionary distant eukaryotes:

1. S. cerevisiae - whose size I can control genetically.
2. C. reinhardtii - whose size I can control with light.

Methodology

I will use an interdisciplinary approach combining:

• Molecular biology
• Quantitative live-cell imaging
• Modelling

This will help develop a quantitative understanding based on measurements of mtDNA replication and degradation.

Dynamic Adaptation

I will then unravel the contribution of the ‘limiting machinery’ regulation to the dynamic adaptation of mtDNA to changing environments. Moreover, by breaking the coupling of mtDNA copy number to cell volume, I will dissect how cell volume and mtDNA copy number determine cell function and aging.

Implications

By identifying the molecular regulation underlying organellar DNA homeostasis, I will address a fundamental question in cell biology and open the door to new intervention strategies for mtDNA misregulation in diseases.