Regulation and roles of nutrient-dependent mitochondrial fusion

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2020
Thesis identifier
  • T15663
Person Identifier (Local)
  • 201560874
Qualification Level
Qualification Name
Department, School or Faculty
  • Mitochondria continuously alter their shape via fusion and fission and interestingly, this dynamic balance is critical for maintaining organelle function and cellular homeostasis. Studies have shown that mitochondria undergo fusion during amino acid starvation-induced autophagy. This mitochondrial response has been proposed to be regulated by MTORC1, a key regulator of nutrient-sensing signalling pathway. However, the mechanism linking MTORC1 and nutrient sensing to mitochondrial hyperfusion has not been fully elucidated.;This project aimed at studying mitochondrial remodelling during nutrient starvation. As a sensor of regulatory amino acids, the role of MTORC1 in the regulation of mitochondrial fusion was studied. In addition, this study also aimed to investigate the kinase-dependent regulation of mitochondrial fusion during amino acid starvation. This project studied the roles of the Ulk1, AMPK and PKA pathways in amino acid starvation-dependent mitochondrial fusion. Using a metabolomics approach, this project also studied changes in cellular metabolism during amino acid starvation-dependent mitochondrial fusion and how hyperfusion could crosstalk with these metabolic changes.;The results in this study indicated that mitochondria undergo remodelling towards a hyperfused state specifically in response to amino acid availability. Importantly, mitochondria surprisingly undergo extensive hyperfusion in response to elevated levels of glutamine (Q), leucine (L) and arginine (R). Contrary to predictions from the current model, mitochondria sensed Q, L and R levels independently of MTORC1. Interestingly, amino acid-dependent mitochondrial hyperfusion critically required the Ulk1/2 autophagy initiation complex. In addition, amino acid-dependent mitochondrial hyperfusion did not require AMPK and PKA-dependent phosphorylation of Drp1. However, amino acid-dependent mitochondrial fusion required the regulators, Optic atrophy 1 (Opa1) and Mitofusin 1 (Mfn1).;Metabolomic analysis revealed both QLR-dependent and fusion-dependent changes in levels of metabolites involved in the urea cycle, Krebs cycle and REDOX balance. Findings in this project suggest putative mechanisms linking amino acid metabolism, mitochondrial dynamics and mitochondrial function.
Advisor / supervisor
  • Pickard, Benjamin
  • Chan, Edmond
Resource Type
Date Created
  • 2020
Former identifier
  • 9912907593202996