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.
Highlights
Mitochondria are cellular organelles with crucial functions in the generation and distribution of ATP, the buffering of cytosolic Ca2+ and the initiation of apoptosis
To determine how phomoxanthone A (PXA) induces apoptosis, we analysed its effect on cellular Ca2+ levels since ionic imbalance can be an apoptotic trigger
There was a delay of about 2–5 min between addition of PXA and increase in [Ca2 +]cyt. Since this pattern of Ca2+ release is similar to that caused by the tyrosine phosphatase inhibitor pervanadate (VO43−) (Fig. S2a), and since tyrosine phosphatase inhibition can induce apoptosis, we tested the effect of PXA on tyrosine phosphorylation
Summary
Mitochondria are cellular organelles with crucial functions in the generation and distribution of ATP, the buffering of cytosolic Ca2+ and the initiation of apoptosis. The respirationdependent mitochondrial network structure rapidly collapses into fragments upon PXA treatment 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. Among their most Mitochondria produce ATP through oxidative phosimportant functions are generation and distribution of phorylation (OXPHOS), which depends on the electron ATP, buffering of cytosolic Ca2+ and, in animal cells, transport chain (ETC) embedded in the inner mitochoninitiation of apoptosis. Disturbance of these or other drial membrane (IMM). In response to certain stimuli, Ca2+ channels in the ER and/or the plasma membrane open to release Ca2+
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