Mitochondrial Stress Response and Cancer

Abstract

Cancer cells survive and adapt to many types of stress including hypoxia, nutrient deprivation, metabolic, and oxidative stress. These stresses are sensed by diverse cellular signaling processes, leading to either degradation of mitochondria or alleviation of mitochondrial stress. This review discusses signaling during sensing and mitigation of stress involving mitochondrial communication with the endoplasmic reticulum, and how retrograde signaling upregulates the mitochondrial stress response to maintain mitochondrial integrity. The importance of the mitochondrial unfolded protein response, an emerging pathway that alleviates cellular stress, will be elaborated with respect to cancer. Detailed understanding of cellular pathways will establish mitochondrial stress response as a key mechanism for cancer cell survival leading to cancer progression and resistance, and provide a potential therapeutic target in cancer.

Keywords: cancer cell survival; cancer progression; heat shock protein 60; mitochondrial stress response; mitochondrial unfolded protein response; therapeutic resistance.

Figure I.. Extramitochondrial roles of HSP60.

Graphical representation of nontraditional roles of HSP60. Cytosolic HSP60 independently interacts with β-catenin, IKK and p53 to induce metastatic signaling, cell survival, and inhibit pro-apoptotic signaling, respectively. Cytosolic HSP60 also binds with Bax at the mitochondrial membrane to inhibit cytochrome c release and inhibit intrinsic apoptosis. On the cell surface, HSP60 interacts with integrin α3β1 to promote breast cancer metastasis. Cell surface HSP60 is also implicated in pancreatic cancer metastasis.

Figure 1.. Key Figure. The activation of mitochondrial stress response and cellular signaling.

Mitochondrial stresses associated with aging, environmental toxins, hypoxia and mitotoxic drugs promote ROS production. ROS damages mitochondrial proteins including the OXPHOS complexes, which may further enhance ROS production. The continued ROS production damages mtDNA. The damaged mtDNA and OXPHOS complexes create an imbalance of the mitochondria-nuclear proteins and induce retrograde signaling. This includes nuclear translocation of the UPR^mt transcription factor ATF5. ATF5 binds to Mitochondrial Unfolded Protein Response Element (MURE) to initiate transcription of UPR^mt genes including HSP60, HSP10 and LONP1. These transcripts are translated and imported into the mitochondria (anterograde signaling). Once within the mitochondria, HSP60 and HSP10 work together to properly fold damaged proteins, and LONP1 cleaves and degrades those proteins that are damaged beyond repair. The UPR^mt proteins promote cell survival by maintaining mitochondrial integrity, thereby preventing cytochrome c release and inhibiting the initiation of intrinsic apoptosis. Abbreviations: HSP = heat shock protein, LONP1 = Lon Protease, ROS = reactive oxygen species, mtDNA = mitochondrial DNA, OXPHOS = oxidative phosphorylation, ATF5 = activating transcription factor 5, MURE = mitochondrial unfolded protein response elements.

Figure 2.. Mitochondrial stress response promotes cancer growth, progression and therapeutic resistance in cancer.

A schematic describing how different stresses induce mitochondrial dysfunction leading to the activation of the mitochondrial stress response, restoration of mitochondrial integrity, cancer cell survival, which subsequently promotes tumor growth and progression.

Figure 3.. Mitochondrial stress response (UPR^mt) regulates various cellular signaling and functions.

A graphical representation depicting the overarching reach of UPR^mt signaling in various cellular functions including bioenergetics, mitochondrial homeostasis, ROS detoxification, cell survival and proliferation.