Journal Club: Cisplatin accumulates in the mitochondria by binding with COX17, and then cause hair cell damage via binding with Myosin IIA.

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Today's journal article

Peng J, Tao G, Chen X, Ai Y, Lai R, Liu W, Hu B, Xu Y, Xie B, Li L. Cisplatin transported by COX17 induces cochlear damage by binding Myosin IIA to regulate cell pyroptosis induced by mitochondrial dysfunction. 

Why I picked this article

Cisplatin is a platinum-based drug for chemotherapy, widely used in various types of cancer. While cisplatin saves lives, it comes with various side effects; one of the common side effects of cisplatin is permanent hearing loss. 

Many studies point to the cause of cisplatin-induced hearing loss to inflammation and mitochondrial stress in the inner ear. Stress in the mitochondria can, in turn, lead to programmed cell death. 

Cisplatin can accumulate in the inner ear organ, the cochlea, to cause damage. So, how does cisplatin get into the inner ear, and why does it accumulate? COX17, cytochrome c oxidase copper shaperon 17, is a protein that interacts with copper in the mitochondria. Previous research has shown that COX17 can facilitate the accumulation of platinum in cancer cells. This research focuses on the role of COX1 and how it relates to a cascade of events in cells that ends in pyroptosis, an inflammatory form of cell death. 

Some of the research findings

Model and readouts
  • Male Sprague-Dawley's rat (~8 week-old) 
    • Cisplatin-induced hearing loss; 16 mg/kg cisplatin (Sigma-Aldrich, USA) via intraperitoneal injection. 
    • Animals assessed 2 days before the injection & 5 days after the injection. 
    • In a later experiment, cisplatin-treated model animals also received siRNA to knock down target genes. siRNA was administered via intratympanic injection. 
  • HEI-OC1 cells (a mouse cochlear-derived cell line) were also used. 
    • siRNA was used to knock down the COX17
  • Outcome measures: 
    • Hearing measured by auditory brainstem response (ABR)
    • Cochlear injury and mitochondrial localisation assessed by H&E histology, qPCR, Western blot, immunofluorescence and flow cytometry. 
5-days cisplatin treatment caused inner ear damage and an increase in inflammation: 
  • Significant hearing loss (elevated hearing thresholds across 4 -64kHz)
  • Hair cell loss
  • Increase in inflammation protein level (NLRP3, IL-1β, IL-18,GSDMD-N)
In HEC-OC1 cells:
  • Cisplatin treatment decreased cell viability and increased levels of inflammation proteins. 
  • Knocking down COX17 reduced mitochondrial cisplatin accumulation, improved cell survival, and lowered pyroptosis signals. 
  • When cisplatin was detected (using anti-cisplatin-modified DNA antibody (#ab103261, abcam)), the cisplatin accumulation in mitochondria was reduced when COX17 was knocked down. 
  • Myosin IIA protein was increased with cisplatin treatment, which was counteracted by COX17 knockdown. 
  • Cisplatin-agarose pull-down experiment to detect proteins that can bind to cisplatin, identified Myosin IIA. 
Focusing on the relationship between COX17, Myosin IIA and cisplatin: 
  • MYH9 knockdown (MYH9 is the gene for producing MyosinIIA) rescued HEI-OC1 cells from cisplatin-induced inflammation. 
  • Also, in vivo model (cisplatin-treated rats), both knockdown of COX17 or MYH9 mitigated the effect of cisplatin. This suggests that COX17 and MYH9 are downstream effectors that mediate the toxicity of cisplatin.  
Taken together, the study has found a new binding partner for cisplatin: once in mitochondria, cisplatin binds non-muscle Myosin IIA. The authors suggest that COX17 aids the accumulation of cisplatin in the mitochondria, and then cisplatin binding to Myosin IIA leads to mitochondrial abnormality and cell death of sensory cells. 
Part of Fig 3I, showing cisplatin-treated HEI-OC1 cells, with cisplatin-DNA antibody labelling (red) and mitochondria (green). Peng et al. 2025

Haruna's takeaway

How interesting - Myosin IIA (according to other studies) is a protein critical for regulating mitochondrial dynamics, such as the splitting of mitochondria (= fission). This is a massive study, with a combination of cisplatin treatment and targeted knockdowns. I am surprised that the knockdown seemed to have worked so effectively in the in vivo rat model. It's quite nice combination of cell line model and the in vivo model in terms of approach. 

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This is Haruna's 82/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.