The mitophagy effector FUNDC1 controls mitochondrial reprogramming and cellular plasticity in cancer cells.
Jie LiEkta AgarwalIrene BertoliniJae Ho SeoM Cecilia CainoJagadish C GhoshAndrew V KossenkovJingjing LiuHsin-Yao TangAaron R GoldmanLucia R LanguinoDavid W SpeicherDario C AltieriPublished in: Science signaling (2020)
Mitochondria are signaling hubs in eukaryotic cells. Here, we showed that the mitochondrial FUN14 domain-containing protein-1 (FUNDC1), an effector of Parkin-independent mitophagy, also participates in cellular plasticity by sustaining oxidative bioenergetics, buffering ROS production, and supporting cell proliferation. Targeting this pathway in cancer cells suppressed tumor growth but rendered transformed cells more motile and invasive in a manner dependent on ROS-mediated mitochondrial dynamics and mitochondrial repositioning to the cortical cytoskeleton. Global metabolomics and proteomics profiling identified a FUNDC1 interactome at the mitochondrial inner membrane, comprising the AAA+ protease, LonP1, and subunits of oxidative phosphorylation, complex V (ATP synthase). Independently of its previously identified role in mitophagy, FUNDC1 enabled LonP1 proteostasis, which in turn preserved complex V function and decreased ROS generation. Therefore, mitochondrial reprogramming by a FUNDC1-LonP1 axis controls tumor cell plasticity by switching between proliferative and invasive states in cancer.
Keyphrases
- oxidative stress
- induced apoptosis
- cell death
- cell proliferation
- dna damage
- reactive oxygen species
- cell cycle arrest
- mass spectrometry
- stem cells
- dendritic cells
- regulatory t cells
- squamous cell carcinoma
- cell cycle
- nlrp inflammasome
- living cells
- pi k akt
- sensitive detection
- cancer therapy
- childhood cancer
- protein protein