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To the Editor We read with great interest the recent paper by Cook et al. [1] in which the authors described a striking mitochondrial vesicle structure induced by some anti-cancer drugs (including Fulvestrant, an antiestrogen drug, or Imatinib, a tyrosine kinase inhibitor) in cultured cancer cells. Using electron microscopy immuno-gold labeling, they further found that some of these mitochondrial vesicles seemed to be labeled with microtubule-associated protein 1 light chain 3 (LC3), a marker for autophagosomes/autolysosomes. Therefore the authors concluded that mitochondria directly donate their membrane to form autophagosomes. We recently reported a similar mitochondrial structure change, which we named mitochondrial spheroids [2,3]. Mitochondrial spheroids are unique mitochondrial structures, which have a ring or cup-like morphology. They look similar to autophagosomes with the interior, or lumen, being surrounded by four mitochondrial membranes and squeezed mitochondrial matrix [3]. Intriguingly, we also demonstrated by confocal microscopy and immuno-gold EM analysis that mitochondrial spheroids are acidic compartments that have acquired lysosomal markers. Mitochondrial spheroids are found in cultured immortalized cells and cancer cells when they are subjected to CCCP-induced mitochondrial depolarization, a widely used mitophagy model in vitro. More importantly, we also found an increase in the number of mitochondrial spheroids in acetaminophen-treated mouse liver. Mechanistically, we found that the formation of mitochondrial spheroids requires mitochondrial fusion proteins mitofusin 1 or mitofusin 2 and is negatively regulated by Parkin, an ubiquitin E3 ligase that induces mitophagy in vitro [4]. The altered mitochondrial structures in the study by Cook et al.

Do mitochondria donate membrane to form autophagosomes or undergo remodeling to form mitochondrial spheroids?