Melittin kills A549 cells by targeting mitochondria and blocking mitophagy flux

ABSTRACT

Melittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells.

KEYWORDS:

• Melittin
• A549 cells
• ROS
• mitochondria damage
• mitophagy
• mitophagy flux
• autophagy
• apoptosis

Acknowledgments

The authors are grateful to the Core Facility of the School of Life Sciences, Lanzhou University (Gansu province, China).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Additional information

Funding

This work was supported by the Scientific and Technological Plan Project of Lanzhou City (No. 2023-2-5, Gansu province, China), Longyuan Youth Innovation and Entrepreneurship Talent Team Project (No. 2022LQTD24, Gansu province, China) and Innovation Star Project of Excellent Graduate Students (No. 2304211025, Gansu province, China).