The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment

Abstract

Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria-primarily, the regulation of mitochondria-mediated apoptosis, Ca²⁺ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.

Keywords: apoptosis; mitochondrial DNA mutation; mitochondrial dynamics; mitophagy; thyroid cancer.

Figure 1

Mitochondrial FAO, ETC. Mutations in mtDNA lead to dysregulation in mitochondrial FAO, ETC, resulting in decreased ATP synthesis and increased ROS production. Effective energy generation (metabolised FA, supplied via FAO and TAC to ETC to produce ATP) is required for tumours’ development and progression. Regulation of the key FAO- (CPT1 and ACC1) and ETC-related genes (NOX4 and COX4) have been suggested as a promising strategy to decrease the efficacy of mitochondrial respiration of cancer cells. FAS—fatty acid synthesis; TG—triglyceride; PDH—pyruvate dehydrogenase; TCA—tricarboxylic acid cycle; I–V—components of mitochondrial ETC (respiratory) chain; Q—ubiquinone, coenzyme Q; C—cytochrome c.

Figure 2

The role of the Hippo pathway in the regulation of mitochondrial biogenesis, mitochondria-mediated apoptosis, mitochondrial dynamics, and mitophagy. When the Hippo pathway is ‘‘off’’, YAP combines with TAZ to target the expression of mitochondria-related genes (to regulate mitochondrial biogenesis, dynamics, and mitophagy). In addition, the components of the Hippo pathway closely interact with the JNK/MAPK pathway to regulate mitochondrial dynamics and mitophagy. Arrows or blunt ends indicate regulation or inhibition, respectively, dashed arrow—skipped steps/components in the pathway. Drp1—dynamin-related protein 1, Mfn1/2—mitofusin1/2, OPA1—optic atrophy protein 1, INF2—inverted formin 2, JNK—c-Jun N-terminal kinase, MAPK—mitogen-activated protein kinase, PGC1α—peroxisome proliferator-activated receptor-a coactivator 1, PINK1—PTEN-Induced Kinase 1, YAP—Yes-Associated Protein 1, TAZ—Tafazzin, BAX—BCL2-Associated X, BCL-xL—Apoptosis Regulator Bcl-X, GRB7—Growth Factor Receptor Bound Protein 7.