Abstract
Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.
Mitochondrial alterations in cancers
Mitochondrial DNA (mtDNA) are exclusively inherited maternally, and 103–104 copies are present in human cells and replicate independently of nuclear DNA (nDNA) (Valiente-Pallejà et al. 2022). Human mtDNA encodes 13 polypeptides critical for respiration and oxidative phosphorylation (OXPHOS), 2 rRNAs and 22 tRNAs involved in mitochondrial protein synthesis (Pearce et al. 2017). Mitochondria play an important role in apoptosis which is essential for cancer development and anticancer agents’ cellular response. In addition, mitochondria generate ATP through the process of OXPHOS and reactive oxygen species (ROS) as products of respiration, and high OXPHOS activity increases mtDNA mutations (Brillo et al. 2021).
Recent studies have shown that mitochondrial functions are involved in different cancer development steps from transformation to drug resistance (Di Gregori et al. 2022). Mitochondrial alterations including mutations, mitochondrial content, expression, and activity of the respiratory chain subunits have been identified in several cancers (Luo et al. 2020). Indeed, the mitochondria play a role as dynamic regulators in malignant cellular processes via metabolic rewiring. The mitochondrial plasticity potential is observed in cancer cells during the tumor development and progression, metastasis dissemination and therapeutic response (Di Gregori et al. 2022).
Pheochromocytomas and paragangliomas: PPGLs
Pheochromocytomas (PCCs) and paragangliomas (PGLs), together PPGLs, are tumors of the chromaffin cells in the adrenal medulla or extra-adrenal paraganglia. By producing high levels of catecholamines (dopamine, norepinephrine and/or epinephrine), they cause severe hypertension resulting in cardio- and cerebrovascular events (e.g. myocardial infarction and stroke), with severe consequences including mortality, if untreated (Pillai et al. 2016, Tabebi et al. 2018, Buffet et al. 2020). Around 10% of all PCCs and >25% of all PGLs result in disseminated metastatic disease. In some hereditary forms, >30% of tumors are malignant (Welander et al. 2011, Tabebi et al. 2018). Malignant PPGLs are difficult to cure, and surgery and conventional chemotherapy are of limited value. New treatment options are therefore sought after.
Nowadays, the genetic background of most PPGLs is well known. They are one of the most heritable tumors, where germline and somatic genetic alterations in non-mitochondrial susceptibility genes are associated with PPGLs development and found in approximately 60% of PPGLs (Pillai et al. 2016). About, 30–40% of the tumors are hereditary and they are caused by hereditary mutations in well-known susceptibility genes (Welander et al. 2011, Fishbein et al. 2017, Tabebi et al. 2022b ). Somatic mutations in hereditary susceptibility genes have been found in around 30% of sporadic PCC/PGLs (Luchetti et al. 2015). Interestingly, those somatic mutations are usually limited to only one gene, indicating that they may be the main driver. However, the cause of many sporadic tumors is still unknown (Burnichon et al. 2010, Welander et al. 2011, Bausch et al. 2017).
Susceptibility genes cause PPGLs
Over the last 30 years, our comprehension of PPGLs genetics has improved significantly, and additional predisposing genes including tumor suppressors and oncogenes are identified for a more precise definition (Welander et al. 2011, Dahia 2014, NGS in PPGL Study Group 2017, Neumann et al. 2019, Jhawar et al. 2022). More than 25 susceptibility genes have been identified (Buffet et al. 2020, Jhawar et al. 2022, Tabebi et al. 2022b) where germline mutations present in around 40% of all cases.
The ‘old’ susceptibility genes
In the beginning of 90s, mutations in RET (rearranged during transfection) and NF1 (neurofibromin 1) genes were the first shown to cause PPGLs and they are known to be involved in the kinase receptor signaling. By 2010, more genes were discovered that belong to the same pathway including MAX (myelocytomatosis-associated factor X), TMEM127 (transmembrane protein 127) and HRAS (Harvey rat sarcoma viral gene homolog) (Buffet et al. 2020, Jhawar et al. 2022).
Before the identification of the genes encoding for the catalytic enzymes in the tricarboxylic acid (TCA) cycle involvement in PPGLs etiology (Fig. 1), VHL (von Hippel-Lindau) gene was the first gene involved in the pseudo-hypoxic pathway. Later, succinate dehydrogenase (SDH) was identified in almost half of the mutated PPGLs including SDHA, SDHB, SDHC, SDH and SDHAF2. The list of genes now also involves FH (fumarate hydratase), HIF2a/EPAS1 (hypoxia-inducible factor alpha) and PHD1/EGLN2, PHD2/EGLN1 (prolyl hydroxylase) (Jhawar et al. 2022).
Dysfunctional tricarboxylic acid (TCA) cycle enzymes in PPGLs: mutations in SDH, FH, MDH, SCS, OGDH and IDH cause HIF1a stabilization. IDH, isocitrate dehydrogenase; OGDC, oxoglutarate decarboxylase; SCS, succinyl-CoA synthetase; SDH, succinic acid dehydrogenase; FH, fumarate hydratase; MDH, malate dehydrogenase; CS, citrate synthase; ACO, aconitase; OXPHOS, oxidative phosphorylation; PPGLs, pheochromocytomas and paragangliomas.
Citation: Endocrine-Related Cancer 30, 1; 10.1530/ERC-22-0217
At the germline level, the most recent statistics have shown that the SDH complex is the most frequently mutated (15–20%); SDHB (10%), SDHD (9%), SDHA (<5%), SDHC (1%) and SDHAF2 (<1%). About 3% of PPGLs have NF1 mutations, 6% and 7% have RET and VHL gene mutations, respectively, and 1–2% have mutations in TMEM127, HIF2A, FH and MAX genes (NGS in PPGL Study Group 2017, Buffet et al. 2020).
The ‘more recently’ discovered genes
Recently, due to the evolution of DNA/RNA sequencing methods, many more genes have been discovered. The new list of genes includes IDH1/2/3B (isocitrate dehydrogenase) (NGS in PPGL Study Group 2017, Remacha et al. 2017), MDH2 (malate dehydrogenase type 2) (Cascón et al. 2015), GOT2 (glutamic oxaloacetic transaminase 2) (Remacha et al. 2017), SLC25A11 (solute carrier family 25 member 11) (Buffet et al. 2018), DLST (dihydrolipoamide S-succinyl transferase) (Remacha et al. 2019) and SUCLG2 (succinyl Co-A ligase G2) (Hadrava Vanova et al. 2022). Those genes encode mitochondrial enzymes catalyzing different TCA cycle reactions (Fig. 1). Mutations can lead to the impairment of the enzymatic activity, thus promoting oncogenesis.
Mutations in FGFR1 (fibroblast growth factor receptor 1), MERTK (tyrosine kinase protooncogene), MET (mesenchymal to epithelial transition) and KIF1Bb (Welander et al. 2014, Toledo et al. 2016) have been observed in small cohorts of PPGLs and seems to be associated with different cellular processes, for example, proliferation, differentiation and metabolic regulation.
The analysis of small cohorts of PPGLs has disclosed newly mutated genes involved in DNA methylation and chromatin remodeling such as H3F3A (histone family member 3A) (Toledo et al. 2016), ATRX (alpha thalassemia/mental retardation-X linked) (Comino-Méndez et al. 2016) and DNMT3A (DNA methyltransferase 3 alpha) (Remacha et al. 2018).
A molecular and genetic analysis of a large cohort including 176 PPGLs (TCGA data) by Fishbein et al. showed the presence of new driver mutations including CSDE1 (cold shock domain containing E1) and UBTF-MAML3 (upstream binding transcription factor mastermind-like transcriptional coactivator 3) (Fishbein et al. 2017), involved in mRNA stability and Wnt signaling (Table 1).
Genetics and clinical profile for the newly discovered forms of cluster 3 in PPGLs
| Gene | Biochemical profile | Gene role | Clinical presentation | Mutation type | Reference |
|---|---|---|---|---|---|
| CSDE1 | Adrenergic | Tumor suppressor gene. Has different functions; mRNA stability, cell type-specific apoptosis, internal initiation of translation and neuronal differentiation |
Sporadic, metastatic and recurrent PPGL | Somatic | Fishbein et al. 2017 |
| UBTF-MAML3 | Adrenergic | Oncogene. Unique hypomethylation profile mRNA overexpression of target gene involved in Wnt signaling pathways |
Sporadic and recurrent PGL. New prognostic factor of poor outcome | Fusion | Fishbein et al., 2017 |
PPGLs, pheochromocytomas and paragangliomas.
Gene expression/pathways
Based on the gene expression patterns and signaling pathways, resulting from hereditary and sporadic PPGLs, three main signatures are distinguished: (1) pseudohypoxic, (2) kinase signaling and (3) Wnt signaling (Dahia et al. 2005, Jimenez et al. 2010, Jochmanová et al. 2013, Fishbein et al. 2017) (Fig. 2).
The subdivision of cluster 1, 2 and 3 genes in PPGLs according to tumor biology. PPGLs, pheochromocytomas and paragangliomas.
Citation: Endocrine-Related Cancer 30, 1; 10.1530/ERC-22-0217
Cluster 1 or the pseudohypoxia cluster includes tumors with mutations in VHL, SDHx, FH, EGLN1/2, IDH3B, MDH2, DLST, SUCLG2 and SLC25A11 genes and the exclusively postzygotic mutations of EPAS1 and IDH1/2 genes (Sarkadi et al. 2022). Malignant PPGLs in cluster 1 are frequent and represent 24% of total PPGL malignancy (Crona et al. 2019, Winzeler et al. 2021). Pseudohypoxia cluster is divided into two sub-clusters: TCA cycle-related and VHL/EGLN1/EPAS1-related mutations. The tumors are characterized by increased expression of genes involved in (pseudo) hypoxia, mitochondrial electron transport chain, Krebs cycle, cell proliferation and angiogenesis.
Cluster 2 includes tumors with mutations in the kinase-signaling pathway, for example, NF1, MAX, MERTK, MET, MYCN, RET, TMEM127, in addition to mutations in BRAF, HRAS and FGFR1 genes that are related only to sporadic PPGLs. 4.1% of malignant PPGLs carry alterations in these genes (Crona et al. 2019, Winzeler et al. 2021). The tumors are characterized by an increased expression of genes involved in cell proliferation, protein synthesis, and kinase signaling.
Schematic connection between mtDNA alterations and PPGL tumorigenesis. ROS, reactive oxygen species; mtDNA, mitochondrial DNA; nDNA, nuclear DNA.
Citation: Endocrine-Related Cancer 30, 1; 10.1530/ERC-22-0217
Cluster 3 was recently highlighted as a separate gene-overexpressing cluster mainly consisting of genes in the Wnt/β-catenin signaling pathway that also includes MAML3 fusion genes and mutations in the CSDE1 gene. About 11.4% of PPGLs in cluster 3 are malignant (Crona et al. 2019, Winzeler et al. 2021).
Mitochondrial alterations in PPGLs
Mutations in nuclear genes encoding for mitochondrial proteins: SDHx
Mutations in nuclear-encoded mitochondrial enzyme genes can cause not only mitochondrial and neurodegenerative diseases but may also be involved in cancer development in many types of cancers (Brandon et al. 2006, Johnson et al. 2017). Those genes are usually responsible for mtDNA integrity and biosynthesis.
SDH (complex II) is formed by four nDNA-encoded subunits, A, B, C and D. As a Krebs cycle enzyme and complex II in the respiratory chain, SDH converts succinate to fumarate and catalyzes the reduction of ubiquinone to ubiquinol, respectively. SDHA contains a flavin adenine dinucleotide that collects electrons from succinate in the TCA cycle and passes the electrons to the iron-sulfur components in SDHB and then to cytochrome b (Cytb) before reaching the ubiquinone-associated components SDHC and SDHD.
Hereditary PPGLs have been mainly linked to mutations in three of the four subunits of succinate dehydrogenase (SDH): SDHB, SDHC and SDHD (Buffet et al. 2020). With regard to SDHA, compound germline mutations in SDHA were initially reported in Leigh syndrome which is a lethal pediatric neurodegenerative disease only. Later, non-compound germline mutations were also reported in patients with paraganglioma (Burnichon et al. 2010, Bakare et al. 2021). Mutations in SDH B, C and D are responsible for retarding the electron flow out of complex II and increasing mitochondrial ROS production (Brandon et al. 2006, Hadrava Vanova et al. 2020). However, mutations in SDHA could block the entry of electrons and remove ROS production. Thus, impairment of ATP and mitochondrial ROS production appear to be the factor that links mitochondrial defects to cancers (Brandon et al. 2006). Actually, there are different proposed mechanisms to link SDHx and PCC/PGL malignancy: (1) SDHx defects trigger succinate accumulation, leading to HIF1a stabilization and promoting cell metabolism, proliferation and angiogenesis (Dahia et al. 2005); (2) Mutated SDHx results in succinate accumulation, inhibits DNA demethylase and silences the expression of different tumor suppressor genes (Xiao et al. 2012); or (3) Defects in SDHx result in an increase in ROS, and the resultant DNA damage and genomic instability induce tumorigenesis (Hadrava Vanova et al. 2021). The biochemical phenotype of SDHx-mutated tumors is defined by high level of dopamine and or norepinephrine. PPGLs associated with SDHC and SDHD mutations are often seen in the head and neck, whereas SDHB-mutated PPGLs are mostly found in the abdomen (Kavinga Gunawardane & Grossman, 2017). SDHB-mutated PPGLs have an incidence of metastasis of 30%, while SDHA-, SDHC- and SDHD-mutated PPGLs have an incidence of metastasis of only 0–4% (Sarkadi et al. 2020). Nevertheless, the high metastatic risk of SDHB-related PPGLs remains mainly unknown (Buffet et al. 2020).
Of note, the oxygen consumption in SDHB-mutated pheochromocytomas is low and associated with succinate accumulation leading to HIF1a stabilization and the transactivation of target genes via the HIF complex. Thus, metabolic rewiring can shift from aerobic glycolysis to a dependence on glutamine (Saxena et al. 2015, Sarkadi et al. 2020, Tabebi et al. 2022a ). Also, cells can consume extracellular pyruvate and activated pyruvate carboxylase gene that diverts glucose-derived carbons into aspartate biosynthesis (Cardaci et al. 2015, Lussey-Lepoutre et al. 2015). Furthermore, in vitro studies showed that the flux to the TCA cycle had increased in SDHB-mutated chromaffin cells promoting OXPHOS (Sarkadi et al. 2020, Tabebi et al. 2022a ).
Mitochondrial DNA aberrations
Compared with nuclear DNA repair machinery, the mtDNA machinery is less efficient (Rong et al. 2021). Thus, impairment of the mtDNA repair machinery may increase the accumulation of mitochondrial alterations. Moreover, mtDNA defects can result in response to mtDNA copy number alterations, mitochondrial point mutations and deletions, mitochondrial dysfunction and cell viability changes. According to human mitochondrial genome database (Mitomap; http://www.mitomap.org/), around 200 mtDNA mutations are associated with human diseases.
Point mutations
Several mutations in nDNA-encoded mitochondrial genes are associated with cancer which leads to the possible contribution of mtDNA mutations to cancer etiology. mtDNA mutations, in the non-coding and coding regions, have been identified in different human tumors. The frequency of somatic mtDNA mutations differs between cancer types and ranges from 13% in glioblastoma, 17% in pheochromocytoma/paraganglioma to 63% in rectal adenocarcinomas and 73.9% in breast cancer (Larman et al. 2012, Pérez-Amado et al. 2020, Tabebi et al. 2022b ). Primarily, the majority of the mtDNA mutations appeared to be homoplasmic (same sequence in all wild type or mutated mtDNA molecules) although heteroplasmy (different mtDNA sequence in the same cell) may also contribute to heterogeneous mitochondrial morphologies and cancer metastasis (Kenny et al. 2017).
At the end of the 90s, Horton et al. identified a 294 nucleotide in-frame deletion in the MT-ND1 in 50% of the studied renal carcinoma patients who developed severe mitochondrial diseases and potential involvement in cancer (Horton et al. 1996).
In 2005, Petros et al. found heteroplasmic T8993G (L156R) germline mutation in the ATP6 gene in prostate cancer patient and demonstrated its tumorigenic ability in a nude mouse. The mutant model was found to induce enhanced ROS production, affecting the transcription and angiogenesis factors and generating seven-fold larger tumors than the wild type. This observation made the first causal link between cancer and mtDNA alterations (Petros et al. 2005).
Previously, we have been reporting that Dloop, non-coding control mtDNA region, is in-frequently mutated (8%) in PPGLs (Tabebi et al. 2022b ). Notably, many tumors showed higher frequency, for example, colorectal tumors (44%), thyroid tumors (49%) and prostate cancer (88%) (Brandon et al. 2006, Hsu et al. 2016, Tabebi et al. 2022b ). The coding region represents the subunits of the electron transport chain complex (NADH dehydrogenase (complex I), cytochrome b (complex III), cytochrome c oxidase (complex IV) and ATPase (complex V)). Mutation analysis of the coding region showed mutations in 23% of PPGL, 52% of thyroid tumors, 23% of papillary thyroid carcinomas and 19% of prostate tumors (Brandon et al. 2006, Tabebi et al. 2022b ) (Table 2).
Summary of mitochondrial variants and known pathogenic mitochondrial mutations associated with PPGLs and other cancers
| Gene | Mutation | Protein variation | Mutation type | Phenotype | |
|---|---|---|---|---|---|
| Complex I | ND1 | 3563G>A | Trp86* | Somatic | PPGL |
| ND1 | 4164A>C | Met286Ile | Somatic | PPGL | |
| ND2 | 4789G>A | Gly107Glu | Somatic | PPGL | |
| ND4 | 12068A>G | Met437Val | Germline | PPGL | |
| ND5 | 12338T>C | Met1Thr | Germline | PPGL and colon cancer | |
| ND5 | 13135G>A | Ala267Thr | Germline | PPGL, cervical, and head and neck cancers | |
| ND5 | 13345G>A | Ala337Thr | Somatic | PPGL | |
| ND5 | 13498G>A | Gly388Ser | Somatic | PPGL | |
| ND6 | 14603GinsT | Ser24Tyrfsx11 | Somatic | PPGL | |
| Complex III | COXIII | 9349T>C | Leu48Pro | Unknown | PPGL |
| COXIII | 9553G>A | Trp116* | Somatic | PPGL | |
| Complex IV | CYB | 15471T>C | Leu24Ser | Germline | PPGL |
| CYB | 15672T>C | Met309Thr | Germline | PPGL, breast and thyroid cancers | |
| CYB | 15789C>T | Thr348Ile | Unknown | PPGL and breast cancer | |
| Complex V | ATP8 | 8466A>T | His34Leu | Germline | PPGL |
| rRNA and tRNA | rRNA16s | 2222T>C | Non-coding | Germline | PPGL and pancreatic cancer |
| rRNA 16s | 1969G>A | NA | Somatic | PPGL | |
| tRNAAsn | 5658T>C | NA | Germline | PPGL | |
| Non-coding region | Dloop | 16093T>C | Non-coding | Germline | PPGL, breast, thyroid and prostate cancers |
| Dloop | 16076C>T | Non-coding | Germline | PPGL | |
| Dloop | 16183delA | Non-coding | Somatic | PPGL and colon cancer | |
| Dloop | 16218C>T | Non-coding | Germline | PPGL, ovarian and prostate cancers | |
| Dloop | 16093T>C | Non-coding | Germline | PPGL, breast, thyroid and prostate cancers | |
| Dloop | 16183delA | Non-coding | Germline | PPGL and colon cancer | |
| Dloop | 16076C>T | Non-coding | Germline | PPGL |
PPGLs, pheochromocytomas and paragangliomas.
Certain mutations in the coding region of mtDNA, mainly complex I and III, have pro-tumorigenic effects and metastatic potential by producing oxidative phosphorylation defects and ROS accumulation (Ishikawa et al. 2008, Smith et al. 2020). However, mutations in non-coding region of the mtDNA do not have a direct pathogenic implication.
Notably, the T16189C transition is a widely studied mutation and generates a variable length polycytosine tract (poly-C) that has been associated with pathogenesis. It has been reported that it interferes with the mtDNA replication mechanism and thus, reduces mitochondrial copy number (Liou et al. 2010, Saha et al. 2021).
Deletions
The most common mtDNA deletion associated with variety of human diseases, aging and an increased risk of cancer is the deletion of a 4977-bp fragment (Chen et al. 2011, Guo et al. 2017, Yusoff et al. 2019). The ΔmtDNA4977 occurs in the major arc of the mitochondrial genome and is located between nucleotides 8470 and 13,477 and contains five tRNA genes (tRNAGly, tRNAArg, tRNAHis, tRNASer and tRNALeu) and four genes, encoding for some of the subunits of complex I (ND3, ND4, ND4L, partial ND5). One gene encodes a subunit of complex IV (COIII) and one gene encodes a subunit of complex V (ATPase8), generating a shorter mitochondrial genome that leads to the impairment of the OXPHOS and a decrease in ATP production and to abnormal ROS generation (Yusoff et al. 2019).
Similar to mitochondrial diseases, for example, Kearns–Sayre syndrome, Pearson syndrome, Leigh syndrome, approximately 27% of PPGLs display multiple large deletions, resulting in the loss of several protein-encoding genes and some tRNA genes (Goldstein & Falk, 1993, Katada et al. 2013, Carreño-Gago et al. 2019, Tabebi et al. 2022b ). Neuhaus et al. showed that mtDNA deletion in adrenal medulla and cortex could be induced by the catecholamine metabolism and result in mitochondrial dysfunction (Neuhaus et al. 2014, 2017). The co-authors demonstrate that dopamine metabolism, particularly its degradation via monoamine oxidase (MAO), is detrimental to the integrity of mtDNA and is likely the cause of the increased accumulation of deletions in dopaminergic cells.
Copy number
mtDNA copy number variations are frequently described in cancer (Tasdogan et al. 2020). Elevated mtDNA content has been observed in primary head and neck squamous cell carcinoma, papillary thyroid carcinoma and endometrial cancer (Su et al. 2016, Sun et al. 2016, Wang et al. 2018), in contrast to pheochromocytomas, breast cancer and gastric cancer, which all showed mtDNA depletion (Weerts et al. 2016, Zhu et al. 2017, Tabebi et al. 2022b ).
Indeed, PPGLs presented a mitochondrial depletion in 86.5% of all analyzed samples (74 PPGLs). Interestingly, the mtDNA content was 3.8-fold lower than in the normal adrenal medulla (Tabebi et al. 2022b ).
The mtDNA copy number is associated with the incidence of driver mutations causing carcinogenesis (Reznik et al. 2016). Decreased mtDNA copy number can be related to mutations in the Dloop, impairment of ATP production, level of transcription of mtDNA genes and chromosome instability, which can lead to tumorigenesis (Errichiello & Venesio 2018). However, increased mtDNA copy number can be a result of the mitochondrial dysfunction or a mutation in the nuclear genes involved in mtDNA integrity, as a compensatory response to sustain mitochondrial function (Filograna et al. 2021). Of note, the mtDNA copy number can influence the level of transcription of mtDNA genes, but the correlation is not applicable to all cancer types (Reznik et al. 2016).
Gene expression
Recently, using RNA-sequencing data revealed lower expression of mtRNA in tumors (relative to normal tissue) across a majority of cancer types (breast, head and neck, liver, bladder) (Reznik et al. 2017). However, few cancers present high mtDNA compared to the nDNA expression (pheochromocytomas and paragangliomas, kidney chromophobe) (Reznik et al. 2017, Tabebi et al. 2022b ). Interestingly, in PPGL tumors and across all the highly expressed mtDNA genes, MT-ND2/ND6 (two subunits of complex I) was expressed with low levels. Several studies studying the gene expression profiling of complex I showed that the mt genes are expressed differently in patients compared to controls (Salehi et al. 2014, van der Lee et al. 2015). mtDNA-encoded subunits are transcribed in a polycistronic way and are regulated by the same promoter (except for ND6). However, the differences in complex I gene expression response could be due to post-transcriptional regulatory mechanisms and/or differences in mRNA stability among mtDNA-encoded genes. Additionally, nuclear gene expression and transcriptional element of OXPHOS subunits and assembly factors could be factors for the observed changes in the transcript levels. The regulation of complex I subunit expression is more complex, than being globally co-regulated (Salehi et al. 2014).
PPGL treatment
The treatment approach for PPGLs is determined by patient characteristics (e.g. age, co-morbidities) and tumor aspects (e.g. primary tumor location, tumor growth rate, local and distant dissemination, hormone and genetic profile). Surgery with effective perioperative catecholamine blocking and cardiovascular monitoring is the gold standard of therapy for PCCs and functional PGLs. While only 10–20% of PPGLs are considered to be malignant and metastasize, the currently existing tools to predict which ones are insufficient. Several histopathologic scoring systems have been proposed and in 2002, Thompson developed the first pathology scoring system, PCC of adrenal gland scaled score (PASS). PASS is a scoring system based on histological features including capsular/vascular invasion, mitotic rate and necrosis (Thompson 2002). Benign tumors present a PASS of <4. However, because of the inconsistent result, a new scoring system combining biochemical, pathological and clinical data has been proposed. Kimura et al. developed the grading system for adrenal pheochromocytoma and paraganglioma (GAPP). GAPP scores the tumors based on different criteria: catecholamine type, cellularity comedo-type necrosis, capsular/vascular invasion, Ki67 labeling index and histological pattern. This system separates PPGLs into poorly differentiated (PD), moderately differentiated (MD) and well-differentiated (WD) (Kimura et al. 2014). Therefore, even patients with PPGLs having no signs of malignancy are recommended to be followed up for a couple of years (Plouin et al. 2016). Patients with malignant PPGLs are difficult to cure, and the treatment options are limited and require a personalized approach. Surgery is of limited value in metastatic tumors and conventional chemotherapy has not been shown to be successful due to the slow growth and spread rate of these tumors. Standard therapy is used as palliative adjunct for PPGLs such as chemotherapy (CVD or temozolomide), radionuclide therapy (131I-MIBG, 177Lu-DOTATATE), tyrosine kinase inhibitors (sunitinib, cabozantinib) and immunotherapy (Nölting et al. 2019b, Jhawar et al. 2022). Thus, very few effective medical treatment options are available and there is a need for drugs to combat metastasizing PPGLs. Since the genetic background of most of these tumors is now known, the question arises whether this knowledge can be used in order to identify gene and mutation-specific drugs.
Based on signaling pathway classification, PPGLs from cluster 1 can be treated with PARP (polyADP-ribose polymerase) inhibitors (mainly for SDHx tumors) (e.g. olaparib) (Nölting et al. 2019a) and HIF inhibitors (mainly for HIF2a) (e.g. belzutifan) that are under evaluation in clinical trials (Wang et al. 2022). For cluster 2 PPGLs, PDL1 inhibitors (e.g. pembrolizumab) (Jimenez et al. 2020) and tyrosine kinase inhibitors (e.g. sunitinib) (Toledo & Jimenez 2018, Nölting et al. 2019b) are currently under evaluation in clinical trials. Unfortunately, there are no targeted therapies for cluster 3, Wnt signaling PPGL (Jhawar et al. 2022). Our recent study has shown that GLUD1 (glutamate dehydrogenase) inhibitors can be a potential therapeutic target in SDHB-mutated PPGLs for example, purpurin and R162 (purpurin analog) (Tabebi et al. 2022a).
Due to pathogenic variants in mtDNA- or nDNA-encoding mitochondrial proteins, dysfunction of the mitochondrial electron transport chain (ETC) and oxidative phosphorylation can result in different mitochondrial diseases and cancers (Luo et al. 2020). In addition, ROS accumulation, insufficient energy generation and dysregulation of apoptosis can manifest in different cells. So, the current treatment options and the existing clinical trials aim to enhance mitochondrial function and treat the consequence of mitochondrial dysfunction. These treatments include: (1) agents improving ETC function (coenzyme Q10, idebenone, riboflavin), (2) agents increasing substrate supply to respiration (dichloroacetate, thiamine), (3) antioxidants (lipoic acid, RP103, EPI-743), (4) agents enhancing mitochondrial biogenesis (bezafibrate, RTA408, resveratrol, AICAR) and (5) cardiolipin protection (elamipretide) (Table 3).
Agents used for treating different mitochondrial dysfunction
| Targeted function | Agent | Mechanisms | Ongoing clinical trials |
|---|---|---|---|
| Improve electron transfer chain function | Ubiquinone (CoQ10) Ubiquinol (CoQ10 |
Energy carrier between complexes I and III and complexes II and III | |
| Idebenone | CoQ10 analog with higher efficacity | ||
| Riboflavin | Flavin adenine dinucleotide (FAD) precursor, a key building block in complexes I and II | ||
| Increase substrate supply to respiration | Dichloroacetate (DCA) | Increase pyruvate dehydrogenase activity and subsequently increase the catabolism of pyruvate to acetyl CoA | |
| Thiamine (vitamin B1) | Increase pyruvate dehydrogenase activity and subsequently increase the catabolism of pyruvate to acetyl CoA | ||
| Antioxidative activity | Lipoic acid | Important factor for pyruvate and ketoglutarate dehydrogenase and present an antioxidant action | |
| RP103 | Cysteamine bitartrate delayed-release capsules. Increase cysteine availability and thereby increase the intracellular glutathione levels |
Leigh and other mitochondrial diseases, ongoing clinical study (https://clinicaltrials.gov/ct2/show/NCT02023866) | |
| EPI-743 | Para-benzoquinone analog. Protection against ROS accumulation and restore intracellular glutathione reduction | Leigh disease, ongoing clinical study (https://clinicaltrials.gov/ct2/show/NCT02352896)Mitochondrial diseases, ongoing clinical study (https://clinicaltrials.gov/ct2/show/NCT01642056) | |
| Enhance mitochondrial biogenesis | Bezafibrate | Active PGC1α by activating PPAR | Mitochondrial myopathy, ongoing clinical study (https://clinicaltrials.gov/ct2/show/NCT02398201) |
| RTA 408 | Synthetic isoprenoid. Active PGC1α by activating NRF2 |
Mitochondrial myopathy, ongoing clinical study (https://clinicaltrials.gov/ct2/show/NCT02255422) | |
| Resveratrol | Active PGC1α by activating sirtuins (e.g., SIRT1) | ||
| AICAR (aminoimidazole carboxamide ribonucleoside) | Active PGC1α by activating AMPK | ||
| Cardiolipin protection | Elamipretide | Binds to cardiolipin and prevents its oxidation | Mitochondrial myopathy, ongoing clinical study (https://clinicaltrials.gov/ct2/show/NCT02367014) |
Furthermore, gene therapy has been achieved using mitochondrial gene delivery by AAV (adeno-associated virus) in Leber hereditary optic neuropathy (LHON) where ND4 mutation is responsible for around 70% of all cases. In fact, the mitochondrial gene can be carried by the AAV, and the viral capsid VP2 can be fused with a mitochondrial-targeting sequence to direct the AAV to the mitochondria and induce ND4 expression. The expression of the wild-type ND4 on the mutant ND4 cells has been shown to be restoring the ATP synthesis (increase by 48%) with a proper translated ND4 in cells (Yu et al. 2012).
Conclusions
Over the past 3 decades, the genetic background of PPGL has unfolded and allows a better understanding of PPGL tumorigenesis and follow-up which have led to novel potential prognostic factors and therapeutic options. PPGLs are heterogeneous and rare tumors that should not be treated similarly. We believe that personalized and precision medicine are the best strategy for patients. Cancer cells can present mitochondrial alterations affecting not only metabolism but also tumor development as well. In this review, we have discussed the different nuclear and mitochondrial alterations observed in cancer and mainly in PPGL (mutations, deletions, copy number and gene expression) (Fig. 3). Despite the prevalence of these alterations in different malignancies, their role remains unclear. Thus, better understanding of the mitochondrial dysfunction role can improve the therapeutic strategy in cancer.
Declaration of interest
The authors declare no conflict of interest.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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