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Cell Death Dis. 2018 Feb 19;9(3):286. doi: 10.1038/s41419-018-0312-8.

The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane.

Author information

1
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
2
Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
3
Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
4
Institute of Anatomy I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
5
Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.
6
Center for Advanced Imaging, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
7
Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
8
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
9
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany. sebastian.wesselborg@uni-duesseldorf.de.
10
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany. bjoern.stork@uni-duesseldorf.de.

Abstract

Mitochondria are cellular organelles with crucial functions in the generation and distribution of ATP, the buffering of cytosolic Ca2+ and the initiation of apoptosis. Compounds that interfere with these functions are termed mitochondrial toxins, many of which are derived from microbes, such as antimycin A, oligomycin A, and ionomycin. Here, we identify the mycotoxin phomoxanthone A (PXA), derived from the endophytic fungus Phomopsis longicolla, as a mitochondrial toxin. We show that PXA elicits a strong release of Ca2+ from the mitochondria but not from the ER. In addition, PXA depolarises the mitochondria similarly to protonophoric uncouplers such as CCCP, yet unlike these, it does not increase but rather inhibits cellular respiration and electron transport chain activity. The respiration-dependent mitochondrial network structure rapidly collapses into fragments upon PXA treatment. Surprisingly, this fragmentation is independent from the canonical mitochondrial fission and fusion mediators DRP1 and OPA1, and exclusively affects the inner mitochondrial membrane, leading to cristae disruption, release of pro-apoptotic proteins, and apoptosis. Taken together, our results suggest that PXA is a mitochondrial toxin with a novel mode of action that might prove a useful tool for the study of mitochondrial ion homoeostasis and membrane dynamics.

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