Analysing the mechanism of mitochondrial oxidation-induced cell death using a multifunctional iridium(III) photosensitiser

Nat Commun. 2021 Jan 4;12(1):26. doi: 10.1038/s41467-020-20210-3.

Abstract

Mitochondrial oxidation-induced cell death, a physiological process triggered by various cancer therapeutics to induce oxidative stress on tumours, has been challenging to investigate owing to the difficulties in generating mitochondria-specific oxidative stress and monitoring mitochondrial responses simultaneously. Accordingly, to the best of our knowledge, the relationship between mitochondrial protein oxidation via oxidative stress and the subsequent cell death-related biological phenomena has not been defined. Here, we developed a multifunctional iridium(III) photosensitiser, Ir-OA, capable of inducing substantial mitochondrial oxidative stress and monitoring the corresponding change in viscosity, polarity, and morphology. Photoactivation of Ir-OA triggers chemical modifications in mitochondrial protein-crosslinking and oxidation (i.e., oxidative phosphorylation complexes and channel and translocase proteins), leading to microenvironment changes, such as increased microviscosity and depolarisation. These changes are strongly related to cell death by inducing mitochondrial swelling with excessive fission and fusion. We suggest a potential mechanism from mitochondrial oxidative stress to cell death based on proteomic analyses and phenomenological observations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Cross-Linking Reagents / chemistry
  • Energy Transfer
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Iridium / pharmacology*
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Oxidation-Reduction / drug effects
  • Photosensitizing Agents / pharmacology*
  • Proteome / metabolism
  • Reactive Oxygen Species / metabolism
  • Viscosity

Substances

  • Cross-Linking Reagents
  • Mitochondrial Proteins
  • Photosensitizing Agents
  • Proteome
  • Reactive Oxygen Species
  • Iridium