Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis

Abstract

In order to support growth, tumor cells reprogram their metabolism to simultaneously up-regulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here, using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 over-expressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Over-expression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signaling.

The expression of brown fat‐associated proteins in colorectal cancer and the relationship of uncoupling protein 1 with prognosis

“…In another study, the overexpression of uncoupling protein 3, a close family member of UCP1, reduced the growth of skin cancer in mice as a result of constitutive oxidation of substrates and nutrients that are essential for maintaining tumour growth, without simultaneous ATP production . Furthermore, mitochondrial uncoupling blocked the activation of AKT serine/threonine kinase 1 (AKT) in mice thereby limiting proliferation and tumorigenesis .…”

“…38 In another study, the overexpression of uncoupling protein 3, a close family member of UCP1, reduced the growth of skin cancer in mice as a result of constitutive oxidation of substrates and nutrients that are essential for maintaining tumour growth, without simultaneous ATP production. 39 Furthermore, mitochondrial uncoupling blocked the activation of AKT serine/ threonine kinase 1 (AKT) in mice thereby limiting proliferation and tumorigenesis. 39 Therefore, UCP1 could inhibit tumour growth by modulating and disrupting the metabolism of mitochondrion, which would lead to loss of nutrients, catabolism, disturbance of the cellular membrane and AKT inhibition (Supporting Information Fig.…”

“…39 Furthermore, mitochondrial uncoupling blocked the activation of AKT serine/ threonine kinase 1 (AKT) in mice thereby limiting proliferation and tumorigenesis. 39 Therefore, UCP1 could inhibit tumour growth by modulating and disrupting the metabolism of mitochondrion, which would lead to loss of nutrients, catabolism, disturbance of the cellular membrane and AKT inhibition (Supporting Information Fig. S11).…”

Oxidative and nitrosative stress during pulmonary ischemia-reperfusion injury: from the lab to the OR

“…• NO further reacts with O 2 •− to form ONOO − which inhibits all mitochondrial complexes (24). There is some evidence from small animal models that cyclosporine treatment might prevent assembly of the mPTP, although a larger meta-analysis failed to show any significant effect (25).…”

Chewing the fat for Akt1 inhibition and oncosuppression

“…3 In a recent publication, we showed that the mechanism of cancer prevention in K5-Ucp3 mice occurs through a novel mechanism of metabolic regulation of thymoma viral proto-oncogene 1 (protein kinase B, best known as Akt1) signaling. 4 To narrow down the possible mechanisms by which Ucp3 overexpression might antagonize tumorigenesis, our first step was to distinguish between effects on tumor initiation and tumor promotion. We bred K5-Ucp3 mice with the "pre-initiated" Tg.AC mouse strain, a transgenic strain that harbors an oncogenic mutation in the Harvey rat sarcoma virus oncogene (Hras), 5 and found that K5-Ucp3/Tg.AC mice are still dramatically protected from tumor formation, leading us to focus on the effect(s) of Ucp3 overexpression on tumor promotion.…”