Pleiotropic regulation of mitochondrial translational factors in governing proliferation, apoptosis and metastasis during cancer progression

Table 1 Role of dysregulated mitochondrial translation factors in various cancers

No.	Cancer	Samples				Translation factor involved	Expression	Mechanism of action	Techniques and assays performed	Application in clinical settings	Ref.
		Cell lines	Clinical samples		Animal models
			Control	Patients
1	HNSCC	HaCaT, HN8, HN12, HN13, HN22	NA	n = 6	NA	MRPL11	Downregulated	Impaired mitochondrial translation due to reduced expression of MRPL11 leads to defective synthesis of mitochondrial-encoded proteins (e.g., COII), which in turn impairs OXPHOS. This defect potentially forces a metabolic shift to aerobic glycolysis (Warburg effect), aiding tumor survival and progression, particularly in metastatic sites	Western blotting, qRT-PCR, wound healing assays	MRPL11 downregulation and mitochondrial translation defects may serve as biomarkers for HNSCC progression and metastatic potential	[13]
2	LC and BC	A549, CCL64, NCI-H446, MCF7, MDA-MB-453, MDAMB-231 and 293T	NA	NA	Nude mouse (n = 5)	TUFM	Upregulated	Loss of TUFM induces EMT and metastasis of lung cancer cells via a mechanism involving activation of the AMPK/GSK3β/β-catenin pathway	Cell migration assays, colony formation, cell cycle analysis, BrdU cell proliferation assay; qRT-PCR; western blotting and immunofluorescent staining, lentiviral transduction, analysis of glycolytic activity, measurement of cellular ROS; nuclear extraction; ATP and NAD1/NADH quantification; measurement of enzyme activity in complex I and complex IV, tissue microarray; IHC	NA	[31]
3	HNSCC	PCI-13, UDSCC2, SCC90, UMSCC22b	NA	n = 23	NA	TUFM	Upregulated	TUFM, together with NLRX1, forms a mitochondrial complex that: (1) Promotes beclin-1 polyubiquitination; (2) Disrupts beclin-1 and rubicon interaction (which otherwise suppresses autophagy); and (3) Promotes ER stress signaling (eIF2α phosphorylation, UPR activation). This autophagy induction counteracts the anti-proliferative effects of EGFR inhibitors	RNAi-based protein expression knockdown and plasmid transfection, Western blots and co-immunoprecipitation; laser confocal imaging and colocalization analysis, TMA analysis	Increased p62 expression post-treatment is associated with poor response to cetuximab, suggesting: (1) p62 could serve as a predictive biomarker for cetuximab response; and (2) Targeting autophagy (e.g., TUFM, Beclin-1 interaction) may improve therapeutic response	[34]
4	Myc-driven lymphoma	Eμ-myc lymphoma cells (murine), Ba/F3 cells, R26-MERT2 MMECs, Raji, Ramos, Namalwa, Daudi (human Burkitt’s lymphoma)	NA	NA	C57BL/6J mice	MRPS5, MRPS27, PTCD3	Upregulated	Activation of c-Myc sensitizes tumor cells to mitochondrial translation inhibition	shRNA library screen, immunoblot analysis; RNA extraction, qRT-PCR, cell growth and apoptosis assay; OCR, ATP and mitochondrial membrane potential measurement; histology and IHC staining	The identification of Myc as a determinant of tigecycline sensitivity provides a new potential indicator for the re-purposing of this antibiotic in the clinical setting	[8]
5	DLBCLs	DHL4, DHL6, Ly1, Toledo, Pfeiffer, K422, Ly4, DHL2, U2932, HBL-1	NA	Not given	NA	MRPL12, GFM1 MRPS7, MRPS25, MRPS22, MRPS5, MRPS9, YARS2 DARS2, MRPL46, TUFM, MRPS16, PUS1	Upregulated	NA	Mitochondria isolation; iTRAQ labeling; deep sequencing; mass spectrometry, RNAi; Tigecycline treatment; viability and proliferation assays; biochemical measurement of respiratory chain enzyme activity; analysis of mitochondrial respiratory chain super complexes; measurement of mitochondrial SRC; determination of mitochondrial superoxide content, analysis of primary DLBCL samples	Tigecycline selectively inhibits mtDNA-encoded protein translation	[50]
6	Colorectal carcinoma	NA	n = 261	n = 261	NA	TUFM	Upregulated	This association indicated that upregulated TUFM expression during the colorectal normal–adenoma–carcinoma sequence may contribute to the transformation from normal mucosa to carcinoma through adenoma	IHC	NA	[35]
7	RCC	786-0 and A-498	NA	NA	BALB/C mice	TUFM	Upregulated	Knockdown of TUFM along with tigecycline treatment in RCC cells leads to reduced cell growth and survival as a consequence of the suppression of essential growth/ survival signaling pathway PI3K/AKT/mTOR	Measurement of cell proliferation; apoptosis and colony formation; western blotting; qRT-PCR; mitochondrial complex activities; measurement of mitochondrial respiration; RNAi of human EF-Tu expression; RCC cancer xenograft mouse model	NA	[36]
8	HCC	MHCC97-H, SMMC-7721	n = 50, TCGA	n = 50, TCGA	Nude mice (BALB/C)	MRPS23	Upregulated	MRPS23 overexpression contributes to: (1) Enhanced proliferation of HCC cells in vitro and in vivo; (2) Associated with larger tumor size, higher TNM stage, and shorter survival; (3) May promote proliferation through enhanced oxidative phosphorylation and changes in tumor metabolism; and (4) No significant role found in migration/invasion	HCC tissue microarray and IHC analysis; lentiviral infection; RNA extraction; qRT-PCR; western blotting; immunofluorescence; cell proliferation and colony formation assay; cell migration and invasion assays	High MRPS23 expression contributes to HCC proliferation and indicates poor survival outcomes	[14]
9	Breast cancer	MCF10A, MCF7, MDA-MB-231, MDA-MB-435, MDA-MB-468	NA	n = 366	NA	NA	Upregulated	RK-33 inhibits DDX3 blocks mitochondrial translation. Consequences: Mitochondrial-encoded proteins; OXPHOS capacity and ATP production; reactive oxygen species (ROS); apoptosis and autophagy; radiation-induced DNA repair; leads to a bioenergetic catastrophe in cancer cells	Cell viability assays; immunoblotting; proteomics; immunofluorescence; mitochondrial translation assay; measurements of oxygen consumption; ATP quantification; mitotracker flow cytometry; measurement of reactive oxygen species; electron microscopy; colony forming assay	RK-33 serves as a radiosensitizer in breast cancer and is a potent inhibitor of mitochondrial translation, which consequently diminishes the mitochondrial OXPHOS capacity and elevates ROS production in cancer cells	[54]
10	Colorectal cancer	RKO (colon cancer), Hela (cervical cancer), SK-Hep-1 (liver cancer), ZR-75-30 (BC), CRL-5803 (LC), MGC-803 (gastric cancer)	NA	n = 60	Nude mice	MRPL33	Upregulated	Role played by MRPL33-L (an isoform of MRPL33) proteins in colon cancer cell growth, cancer development and repress cancer cell apoptosis	Cell growth and colony-survival assay, RNA isolation; qRT-PCR; western blotting and immunoprecipitation, Generation of recombinant lentivirus and MRPL33 minigenes; mitochondria staining; ROS assay; ATP detection and analysis of apoptosis; RNA-seq	NA	[46]
11	LC; cervical cancer; esophageal cancer; bladder cancer	HeLa, H1299, A549, MDA-MB-231, HepG2, SK-MES-1, H460, K562, PC3, HFF (control), 16HBE, PASMC	Not given	Not given	Nude mice	mtEF4	Upregulated	Low mtEF4 increases mt-translation but decreases translational fidelity, leading to low-quality respiratory chain complexes that may degrade or yield less ATP and more ROS, increasing apoptosis risk. High mtEF4, however, boosts respiratory chain complexes production, raising ATP and ROS levels, vital for cellular energy and signaling	RNA extraction; qRT-PCR; western blot; TEM; OCR and ECAR, TCA metabolites assay; BNG and IGA; estimation of mitochondrial ROS production; detection of MMP; ATP assay; tumor growth assay; cell proliferation and apoptosis	NA	[10]
12	GBM	U251MG, U87MG, HaCaT cells (human keratinocyte cell line), GSCs, NSCs	Not given	Not given	NA	TUFM	Upregulated	Nanobody Nb206 binds TUFM interferes with GSCs and GBM cells’ proliferation and viability	Immunoaffinity enrichment (bio-panning); ELISA; mass spectrometry and antigen identification; qRT-PCR; western blotting; cytotoxicity measurements; apoptosis and necrosis, IHC	Nanobody-based targeting may bypass limitations of traditional antibodies, particularly in crossing the blood-brain barrier	[37]
13	Ovarian cancer	SW626, SK-OV-3 (ovarian cancer); HIOEC (normal ovarian epithelial); BJ-5ta (normal fibroblast)	NA	NA	SCID mice	Mitochondrial ribosomes	NA	Tigecycline specifically inhibits translation by mitochondrial ribosome but not nuclear or cytosolic ribosome, leading to mitochondrial dysfunction, oxidative stress and damage, AMPK activation and inhibition of mTOR signaling in ovarian cancer cells	Generation of mitochondrial DNA deficient r0 cell line; qRT-PCR, proliferation, cell cycle and apoptosis analysis, Mito stress test assay, measurement of oxidative stress and damage; xenograft ovarian cancer model	Tigecycline and cisplatin demonstrate synergistic effects in both in vitro and in vivo studies, suggesting potential for overcoming cisplatin resistance in ovarian cancer treatment	[58]
14	Osteosarcoma	MG63, U-2 OS, Saos-2, HOS	NA	NA	SCID mouse	TUFM	Upregulated	Knockdown of TUFM and tigecycline’s anti-cancer activities include inhibition of mitochondrial translation, suppression of Wnt/b-catenin, p21CIP1/WAF1 and miRNA-199b-5p-HES1 AKT pathway; Tigecycline selectively inhibits mitochondrial translation, impairs mitochondrial respiration, induces apoptosis in osteosarcoma cells	Drug and generation of mitochondrial DNA deficient r0 cell line; measurement of proliferation and apoptosis; siRNA knockdown and qRT-PCR; OCR; Measurement of mitochondrial biogenesis; osteosarcoma xenograft in SCID mouse	NA	[53]
15	AML	MOLM13-R1, MOLM13-R2, SU048-R	NA	Not given	NSG mice	MRPS29	NA	NA	Flow cytometric analysis; NSG xenotransplantation; drug treatment; leukemic burden analysis	Inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triple therapy for AML	[52]
16	BC	MCF7, ZR-75-1, BT-474, BT-549, MDA-MB-231, AU565, MDA-MB-361, control cell lines- MCF-10F	NA	NA	NA	NA	NA	GA-TPP+C10 causes: (1) Initial mitochondrial uptake and OXPHOS uncoupling; (2) Complex I inhibition; (3) αKGDHC inhibition; and (4) Induction of a glycolytic shift and AMPK-PGC1α mediated adaptive response. Doxycycline blocks: (1) Adaptive mitochondrial biogenesis by inhibiting mitochondrial translation; and (2) Leads to mitonuclear protein imbalance and synergistic cancer cell death when combined with GA-TPP+C10	MTT assay and crystal violet staining (cell viability); seahorse extracellular flux analysis (OCR and ECAR); qRT-PCR; western blot; flow cytometry (Annexin V/PI apoptosis assay, cell cycle analysis); αKGDHC activity assay; colony formation assay	Combination of a mitochondria-targeted metabolic inhibitor (GA-TPP+C10) and a mitochondrial translation inhibitor (doxycycline) demonstrates selective synergistic killing of breast cancer cells while sparing normal cells	[55]
17	GBM	NHA cells, HA cells, and U-87MG, U-138MG, U-251MG	n = 4	n = 61	Nude mice	MRPS16	Upregulated	MRPS16 over-expression remarkably promotes tumor cell growth, migration and invasion via the PI3K/AKT/Snail axis, which may be a promising prognostic marker for glioma	Western blotting; qRT-PCR; EdU; CCK-8; colony formation; transwell migration and invasion assays; coimmunoprecipitation	MRPS16 over-expression is a promising prognostic marker for glioma	[32]
18	GBM	U251MG, U87MG (mature GBM); NCH644, NCH421k (GSCs); HA cells	Not given	Not given	NA	TUFM	Upregulated	Nanobodies bind target proteins inhibit cell viability, induce apoptosis/necrosis, and reduce cell migration	qRT-PCR; ELISA; IHC; apoptosis/necrosis assays; cell migration assays	NA	[38]
19	GIST	GIST-T1 (KIT exon 11 mutation) and IM-resistant GIST-IR cells (induced via imatinib)	NA	NA	NA	TUFM	Upregulated	TUFM-knockdown decreased the proliferation and migration capacity of GIST-T1 and GIST-IR cells	TUFM silencing plasmids and electric transfection; qRT-PCR; western blotting; cell morphology and fluorescence assessment; cell proliferation and viability assays; wound healing and transwell assays; cell cycle determination	TUFM may serve as an effective target to inhibit early hematogenous metastasis, as well as postoperative recurrence and metastasis in patients with GIST, even in IM-resistant patients	[9]
20	HCC	Hepa 1-6, HepG2	Not given, GEO and TCGA dataset	Not given, GEO and TCGA dataset	C57 mice	MTIF2	Upregulated	MTIF2 suppression enhances apoptosis in HCC by modulating interactions with the apoptosis-inducing factor AIFM1, which can promote caspase3 expression. Also, down-regulation of MTIF2 impaired the proliferative and migratory abilities of HCC cells	Data acquisition and preprocessing; construction of co-expression network; establishment of module-trait relationship; pathway enrichment analysis; identification of hub genes, Cox risk regression and GSEA enrichment analysis; ATP assay; flow cytometry analysis; ELISA; cell viability assay; luciferase reporter assay; western blot analysis and IP	Overexpression MTIF2 impairs drug-induced immunogenic cell death in HCC, and a combination of treatment with MTIF2-knockdown may enhance the effect of chemotherapy	[42]
21	Cholangiocarcinoma	NA	NA	n = 36	NA	MRPL27	Upregulated	MRPL27 mainly involved in the processes of mitochondrial translation elongation, respiratory electron transport, ATP synthesis, and inner mitochondrial membrane organization	Survival analysis; PPI and enrichment, functional enrichment of interacted genes of MRPL27; identification of MRPL27 mutations	Upregulation of MRPL27 in tumor tissues predicted worse OS and DFS in cholangiocarcinoma patients	[15]
22	GBM	COMI, VIPI cells	NA	NA	NA	TUFM, MRPS18A	NA	Genetic inhibition of mitochondrial translation nearly completely abolished gliomasphere formation	Cas9 cell line generation; lentiviral vectors production; generation of knockout cell lines; viability assays; gliomasphere formation assay; cell cycle assay; apoptosis assay; autophagy assays; cryo-EM data and its processing; immunoblotting; immunofluorescence; RNA extraction; qRT-PCR; BNG and IGA assay, respiration assay; mitochondrial membrane potential assessment, lactate assay; competition assay	NA	[39]
23	BC	MCF-7, SKBR3, MDAMB231, MDAMB468, BU 25 TK, SiHa, HeLa, HTB34, SNU 638, AGS, NUGC, NCIH460, A549	NA	NA	NA	MRPS9, MRPS10, MRPS11, MRPS18B, MRPS31, MRPS33, MRPS38, MRPS39	MRPS10 and MRPS31- upregulated	MRPS proteins interact with non-mitoribosomal proteins (e.g., p53, ROS1, ACADSB). Involvement in cancer pathways: PIP3/AKT, MAPK, Wnt, Hedgehog, Estrogen signaling, G2/M transition, apoptosis, NF-κB, circadian rhythm	qRT-PCR, western blotting; MALDI; FPLC, GST pull-down assay; mass spectrometry; network and gene ontology analysis	MRPS10 and MRPS31 could serve as biomarkers or therapeutic targets in breast cancer	[44]
24	RCC	HK-2, 786-O, A498, Caki-2	NA	NA	Nude Mice	NA	NA	Doxycycline selectively inhibits mitochondrial protein translation in RCC cells, causing: (1) Disruption of ETC; (2) Decreased mitochondrial respiration (↓OCR); (3) Apoptosis and reduced proliferation; and (4) Synergistic effect with paclitaxel (a chemotherapy agent)	Cell proliferation and CI measurements; measurement of apoptosis; anchorage-independent colony formation; western blot analyses; qRT-PCR; mitochondrial complex activities; Mito stress assay	Doxycycline is a useful addition to the treatment strategy for RCC, mitochondrial translation inhibition in sensitizing RCC to chemotherapy	[56]
25	BC	NA	n = 291 (TCGA and GTEx databases)	n = 1085 (TCGA and GTEx databases)	NA	MRPL1, MRPL13, MRPS6, MRPS18C, MRPS35, MRPL16, MRPL40	MRPL1, MRPL13, MRPS6, MRPS18C, and MRPS35- upregulated; MRPL16, and MRPL40- downregulated	MRPL16 and MRPL40 were positively associated with survival outcomes, while MRPS18C and MRPS35 were inversely correlated with overall survival. MRPs are involved with cancer pathways like p21WAF1/CIP1, p27Kip1, and p53 for BC progression	Differential expression analysis; genomic alteration and methylation analysis; functional enrichment analysis and protein interaction visualization; survival analysis and prognostic model establishment	MRPs acted as biomarkers in individualized risk prediction and may serve as potential therapeutic targets in BC patients	[45]
26	BC	MCF10A (non-tumorigenic) MCF7 (ER/PR+), MDA-MB-231 (triple-negative)	NA	n = 26	NA	MRPs (MRPS29, MRPS18B, MRPS30, and MRPL11), TSFM, TUFM	Upregulated	Downregulation of MRPs and translation factors impaired mitochondrial translation reduced OXPHOS subunit expression (especially complex I and IV) → altered mitochondrial energy metabolism. Correlation with EMT markers (↑vimentin, ↓E-cadherin) indicates promotion of metastasis and invasiveness	Immunoblotting analyses; qRT-PCR; mitochondrial complex IV activity assays	NA	[11]
27	Liver cancer	Human PLC, HepG2, MDA-MB-468, A549, MCF7, HEK293T	NA	Not given	BALB/C nude mice	GFM2	NA	Translocated mitochondria PHGDH recruits the mitochondrial ribosome recycling factor mtEF4 via ANT2, facilitating subsequent cycles of mitochondrial translation and promoting liver cancer cell progression	RNA extraction; qRT-PCR; western blot; immunoprecipitation; mitochondria isolation, Mitochondrial translation assays; polysome profiling assay; in vitro GST pull-down assay; proliferation assay, immunofluorescence analysis; BNG; oxygen consumption measurements	NA	[41]
28	GBM	COMI and VIPI	NA	NA	NA	NA	NA	Inhibition of mitochondrial translation via binding to the peptidyl-transferase center of the mitoribosome. Impairment of OXPHOS complex assembly leading to GSC viability loss	Cryo-EM analysis of Q/D-mitoribosome interaction, Viability assays; mitochondrial and cytosolic protein synthesis assay, Immunoblotting; UHPLC-MS analysis	Q/D (Synercid®) is approved by the FDA for treating skin infections. The fluorine derivatives (16R)-1e, (16R)-2e, and flopristin are proposed for further in vivo testing against GBM	[40]
29	BC	MCF10A, MCF7, BT474, MDA-MB-361	Not given	n = 89 (METABRIC datasets, TCGA tumors)	MCF7 xenografts and PDX (HCI-017), NSG mice	TUFM	NA	CBFB (through hnRNPK) binds mt-mRNAs and promotes interaction with TUFM. CBFB deficiency impairs mitochondrial translation, ETC dysfunction, ↑glycolysis (Warburg effect), ↑autophagy/mitophagy. Cells become dependent on autophagy for survival, creating a therapeutic vulnerability	Bioinformatic analyses; RIP assay, immunofluorescence staining; confocal microscopy, and super-resolution microscopy; mitochondria fractionation; in situ mitochondrial translation assay; mitochondria stress test and glycolysis stress test; flow cytometry	Combination of PI3K inhibitor (BYL719) + autophagy inhibitor (HCQ) synergistically suppressed tumor growth	[30]
30	BC	MCF-7, MDA-MB-231, MDA-MB-436, SK-BR3	Not given (TCGA)	Not given (TCGA)	BALB/C nude mice	mtEF4	Upregulated	Upregulation of mtEF4 elevates the mitochondrial oxidative phosphorylation, which contributes to the migratory capacities of breast cancer cells. mtEF4 also increases the potential of glycolysis, probably via an AMPK-related mechanism	IHC; qRT-PCR; immunoblot; extracellular flux assay; ATP measurements, Isolation of mitochondria and IGA analysis; transwell assays; GEO and TCGA datasets analysis	The aberrantly upregulated mtEF4 contributes to the metastasis of breast cancer by coordinating metabolic pathways	[61]
31	B-cell lymphoma	Control-OCI-Ly7, OCI-Ly1;	NA	NA	WT mice, B-Tfam mice (Tfam deletion in B cells); Aicda-Tfam mice (Tfam deletion in germinal center B B cells); c-Myc lymphoma model	NA	NA	TFAM regulates mitochondrial transcription and translation in germinal center B cells. Deletion of TFAM: (1) Impairs mitochondrial remodeling; (2) Disrupts actin cytoskeleton; (3) Impairs motility and spatial organization of germinal center B cells; (4) Prevents proper germinal center formation and output; and (5) Inhibits lymphoma development (c-Myc model)	Flow cytometry; confocal and STED microscopy; 5-EU incorporation (RNA synthesis); OPP labeling (mitochondrial translation); spectral flow cytometry (ETC protein profiling); single-cell RNA-seq and V(D)J sequencing; IHC; OCR; adoptive transfer experiments; TFH-B cell co-culture; ELISA for affinity maturation; iGB (induced GC B cell) culture system	TFAM expression/activity as a biomarker for germinal center b cell activation and transformation	[33]
32	AML	NA	NA	n = 41	NA	MRPL10, MRPL22, MRPL11, MRPL54, MRPL12, MRPL16, MRPL20, MRPL24, MRPL28, MRPL38, MRPL57, MRPS18A, MRPS27	Upregulated	NA	Data analysis	Elevated expression of mitochondrial proteins may serve as a potential indicator of relapse risk in patients with AML who have the monocytic FAB subtypes M4 and M5	[51]
33	BC	MCF-10, MD A-MB-468, MD A-MB-453, MD A-MB-231, MCF-7	NA	NA	BALB/C nude mice	MRPS23	Upregulated	Promotes proliferation, migration, and EMT in breast cancer cells	Western blotting; cell migration and invasion assay; qRT-PCR; CCK-8; colony formation assay; transwell migration assays	MRPS23 can be a potential biomarker for aggressive breast cancer subtypes	[43]

HNSCC: Human head and neck squamous cell carcinoma; LC: Lung cancer; BC: Breast cancer; DLBCL: Diffuse large B-cell lymphomas; RCC: Renal cell carcinoma; HCC: Hepatocellular carcinoma; GBM: Glioblastoma multiforme; AML: Acute myeloid leukemia; GIST: Gastrointestinal stromal tumor; NA: Not available; GSC: Glioblastoma stem cell; NSC: Neural stem cell; NHA: Normal human astrocyte; HA: Human astrocyte; ER: Estrogen receptor; PR: Progesterone receptor; TCGA: The Cancer Genome Atlas; NSG: NOD-SCID-Il2rg(-/-); GEO: Gene Expression Omnibus; GTEx: Genotype-Tissue Expression; METABRIC: Molecular Taxonomy of Breast Cancer International Consortium; Tfam: Mitochondrial transcription factor A; MRPL: Mitochondrial ribosomal protein large subunit; TUFM: Mitochondrial elongation factor Tu; MRPS: Mitochondrial ribosomal protein small subunit; PTCD: Pentatricopeptide repeat domain; GFM1: Mitochondrial elongation factor G1; YARS2: Tyrosyl-transfer RNA synthetase 2; DARS2: Aspartyl-transfer RNA synthetase 2; PUS1: Pseudouridine synthase 1; mtEF4: Mitochondrial translation elongation factor 4; MTIF: Mitochondrial translation initiation factor; TSFM: Mitochondrial elongation factor Ts; GFM2: Mitochondrial translation elongation factor G2; COII: Cytochrome c oxidase subunit II; OXPHOS: Oxidative phosphorylation; EMT: Epithelial-mesenchymal transition; AMPK: Adenosine monophosphate-activated protein kinase; GSK3β: Glycogen synthase kinase 3β; NLRX1: NOD-like receptor X1; eIF2α: Eukaryotic initiation factor 2α; EGFR: Eukaryotic initiation factor 2α; UPR: Unfolded protein response PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; TNM: Tumor-node-metastasis; DDX3: DEAD box RNA helicase; ATP: Adenosine triphosphate; ROS: Reactive oxygen species; p21CIP1: Cyclin-dependent kinase interacting protein 1; WAF1: MiRNA-199b-5p-HES1; αKGDHC: Α-ketoglutarate dehydrogenase complex; PGC1α: Peroxisome proliferator-activated receptor gamma coactivator 1α; ACADSB: Acyl-CoA dehydrogenase, short/branched chain B; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; ETC: Electron transport chain; OCR: Oxygen consumption rate; MRP: Mitochondrial ribosomal protein; p21WAF1: P21 wild-type p53-activated fragment 1; CIP1: CDK-interacting protein 1; p27Kip1: P27 kinase inhibitory protein 1; PHGDH: Phosphoglycerate dehydrogenase; ANT2: Adenine nucleotide translocase 2; CBFB: Core binding factor beta; hnRNPK: Heterogeneous nuclear ribonucleoprotein K; mt-mRNA: Mitochondrial messenger RNA; ETC: Electron transport chain; qRT-PCR: Quantitative reverse transcriptase polymerase chain reaction; NAD1: Nicotinamide adenine dinucleotide; NADH: Nicotinamide adenine dinucleotide hydride; IHC: Immunohistochemistry; RNAi: RNA interference; TMA: Tissue microarray; shRNA: Short hairpin RNA; OCR: Oxygen consumption rate; iTRAQ: Isobaric tags for relative and absolute quantitation; SRC: Spare respiratory capacity; DLBCL: Diffuse large B-cell lymphomas; EF-Tu: Elongation factor Tu; RNA-seq: RNA sequencing; TEM: Transmission electron microscopy; ECAR: Extracellular acidification rate; TCA: Tricarboxylic acid cycle; BNG: Blue native polyacrylamide gel electrophoresis; IGA: In-gel activity; MMP: Mitochondrial membrane potential; ELISA: Enzyme-linked immunosorbent assay; siRNA: Small interfering RNA; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; EdU: 5-ethynyl-2’-deoxyuridine; Co-IP: Coimmunoprecipitation; IP: Immunoprecipitation; PPI: Protein-protein interaction; cryo-EM: Cryogenic electron microscopy; MALDI: Matrix-assisted laser desorption/ionisation; FPLC: Fast protein liquid chromatography; GST: Glutathione S-transferase; CI: Combination index; UHPLC-MS: Ultra-high performance liquid chromatography-mass spectrometry; RIP: RNA immunoprecipitation; PLA: Proximity ligation assay; 5-EU: 5-Ethynyluridine; OPP: O-propargyl-puromycin; iGB: Induced germinal center B cell; mtDNA: Mitochondrial DNA; IM: Imatinib mesylate; OS: Overall survival; DFS: Disease-free survival; FDA: Food And Drug Administration; HCQ: Hydroxychloroquine; FAB: French-American-British classification.