Chaiheon Lee^1,2,5, Jung Seung Nam^1,2,5, Chae Gyu Lee^1,2, Mingyu Park^1,2, Chang-Mo Yoo³, Hyun-Woo Rhee³, Jeong Kon Seo^4,* & Tae-Hyuk Kwon^1,2,*

¹Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
²Center for Wave Energy Materials, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
³Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea.
⁴UNIST Central Research Facility, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.

⁵These authors contributed equally: Chaiheon Lee, Jung Seung Nam.

^*Corresponding author

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.