Abstract
Molecules designed to target and accumulate in the mitochondria are an emerging therapeutic approach for cancer and other indications. Mitochondria-targeted redox agents (MTAs) induce mitochondrial damage and autophagy in cancer cells. However, the mechanisms for these molecules to induce mitophagy, the clearance of damaged mitochondria, are largely unknown. Using breast derived cell lines and a series of targeted molecules, mitochondrial dysfunction and autophagy was established to be selective for MDA-MB-231 cancer cells as compared to the non-cancerous MCF-12A cells. Kinetic analyses revealed that mitochondrial dysfunction precedes the activation of autophagy in these cancer cells. To determine the onset of mitophagy, stably expressing mitochondrial mKeima, a mitochondrial pH sensor, cell lines were generated and revealed that these drugs activate lysosomal dependent mitochondrial degradation in MDA-MB-231 cells. Mitophagy was confirmed by identifying the accumulation of a PINK1, mitochondria located in autophagosomes, and the formation of an autophagosome-mitochondria protein (MFN2-LC3-II) complex. These results are the first to demonstrate that mitochondrial redox agents selectively induce mitophagy in a breast cancer cell line and their potential application both as tools for investigating mitochondrial biomechanics and as therapeutic strategies that target mitochondrial metabolism.
Highlights
Mitochondria-targeted redox molecules utilizing triphenylphosphonium (TPP) conjugation are an emerging class of experimental therapeutics to ameliorate cardiovascular disease, neurodegenerative disorder and cancer [1,2,3,4,5]
To determine if different redox moieties conjugated to TPP induce mitochondrial damage and activate autophagy in breast cancer cells, the ΔΨm and autophagic flux were measured in MDA-MB-231 cells exposed to sub-lethal concentrations of MitoQ, Mitotempol (MitoT), Mitochromanol acetate (MitoCA) and Mitoapocynin (MitoApo) (Supplementary Figure 1a) [30]
Our findings provide the first evidence for how molecules that target or accumulate in the mitochondria can selectively damage mitochondria and signal for mitophagic clearance (Figure 6F)
Summary
Mitochondria-targeted redox molecules utilizing triphenylphosphonium (TPP) conjugation are an emerging class of experimental therapeutics to ameliorate cardiovascular disease, neurodegenerative disorder and cancer [1,2,3,4,5]. As cancer cells possess hyperpolarized ΔΨm, TPP conjugates selectively accumulate in the mitochondria of cancer cells by a 10 fold increase as compared to normal cells [3, 9, 10]. In contrast to the beneficial effects demonstrated in normal cells, cancer cells subjected to MitoQ underwent cell cycle arrest, mitochondrial depolarization, enhanced superoxide production and apoptosis [1, 14]. Similar to MitoQ, other TPP-conjugated drugs have demonstrated detrimental effects that were selective for cancer cells as compared to normal cells [2, 15,16,17,18]. The mechanisms that contribute to the cancer cell selectivity of MTAs are not well understood
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