Enforced lysosomal biogenesis rescues erythromycin- and clindamycin-induced mitochondria-mediated cell death in human cells

Paresh Prajapati, Pooja Dalwadi, Dhruv Gohel, Kritarth Singh, Lakshmi Sripada, Khyati Bhatelia, Bhavana Joshi, Milton Roy, Wang Xia Wang, Joe E. Springer, Rochika Singh, Rajesh Singh

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Antibiotics are the front-line treatment against many bacterial infectious diseases in human. The excessive and long-term use of antibiotics in human cause several side effects. It is important to understand the underlying molecular mechanisms of action of antibiotics in the host cell to avoid the side effects due to the prevalent uses. In the current study, we investigated the crosstalk between mitochondria and lysosomes in the presence of widely used antibiotics: erythromycin (ERM) and clindamycin (CLDM), which target the 50S subunit of bacterial ribosomes. We report here that both ERM and CLDM induced caspase activation and cell death in several different human cell lines. The activity of the mitochondrial respiratory chain was compromised in the presence of ERM and CLDM leading to bioenergetic crisis and generation of reactive oxygen species. Antibiotics treatment impaired autophagy flux and lysosome numbers, resulting in decreased removal of damaged mitochondria through mitophagy, hence accumulation of defective mitochondria. We further show that over-expression of transcription factor EB (TFEB) increased the lysosome number, restored mitochondrial function and rescued ERM- and CLDM-induced cell death. These studies indicate that antibiotics alter mitochondria and lysosome interactions leading to apoptotsis and may develop a novel approach for targeting inter-organelle crosstalk to limit deleterious antibiotic-induced side effects.

Original languageEnglish
Pages (from-to)23-36
Number of pages14
JournalMolecular and Cellular Biochemistry
Volume461
Issue number1-2
DOIs
StatePublished - Nov 1 2019

Bibliographical note

Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • Antibiotics
  • Autophagy
  • Lysosome
  • Mitochondria
  • Side effects

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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