Systemic evaluation of MYC dependent mitochondrial activity

Myc is a fundamental master regulator of a large fraction of the transcriptome1, controlling
cell growth and proliferation, together with metabolic adaptation imposed by these
processes. However, while the key role of Myc in signaling and proliferation in development
and immune responses is well studied, how Myc maintains metabolic homeostasis of tissues
under normal and stress conditions2 is less well known. MYC is one of the most commonly
amplified proto-oncogenes in tumours underlying tumorigenesis, also providing essential
models for studying MYC biology3.
A large mitochondrial proteome (>1K members4) cover numerous mitochondrial functions
essential for survival and metabolic homeostasis. The proteome is dynamically regulated
according to cellular needs, but the underlying regulatory mechanisms are poorly
understood. Importantly, Myc-mediated metabolic adaptation is known to involve biogenesis
of the oxidative phosphorylation (OXPHOS) system5, and central carbon metabolism6,7.
However, little is known how other essential mitochondrial functions, such as extensive non-
OXPHOS metabolism, genetic apparatus, morphology dynamics and signalling are controlled
by MYC.
The overarching objective of the proposal is to systematically analyse mitochondrial
dynamics and function during the time course of Myc activation, to test the hypothesis that
multiple mitochondrial activities are essential to Myc-mediated cellular adaptation. This
objective will be achieved by the following aims.
1. Imaging mitochondrial structure and function in in vitro and in vivo Myc induction models.
In vitro (2D/3D) cellular models and tumour tissues with inducible Myc expression
will be used for advanced live-cell imaging techniques, including two-photon confocal
microscopy and FLIM, FRET based biosensors (UCL)8,9.
2. Estimating metabolic fluxes using isotope tracers, including lipidomics. Metabolic Flux
Analysis (MFA) and FBA based modeling of the findings (Crick Institute-UCL)6,7.
3. Transcriptome (RNASeq) analysis of all samples, followed by detailed pathway analysis.
Altogether, these approaches will give fundamental new insight into Myc mediated metabolic
adaptation.