Unraveling the roles and mechanisms of mitochondrial translation in normal and malignant hematopoiesis

Abstract

Due to spatial and genomic independence, mitochondria possess a translational mechanism distinct from that of cytoplasmic translation. Several regulators participate in the modulation of mitochondrial translation. Mitochondrial translation is coordinated with cytoplasmic translation through stress responses. Importantly, the inhibition of mitochondrial translation leads to the inhibition of cytoplasmic translation and metabolic disruption. Therefore, defects in mitochondrial translation are closely related to the functions of hematopoietic cells and various immune cells. Finally, the inhibition of mitochondrial translation is a potential therapeutic target for treating multiple hematologic malignancies. Collectively, more in-depth insights into mitochondrial translation not only facilitate our understanding of its functions in hematopoiesis, but also provide a basis for the discovery of new treatments for hematological malignancies and the modulation of immune cell function.

Keywords: HSC; Hematologic malignancy; Hematopoiesis; Immune cell; Mitochondrial translation; T cell.

Fig. 1

The human mitochondrial translation cycle Protein synthesis consists of four distinct steps: initiation, elongation, termination, and recycling. Mitochondria employ a simplified set of translation factors to perform the translation process. During initiation, mtIF2 and mtIF3 play crucial roles. mtIF2 prevents tRNA binding to the ribosomal A site through a specific structural domain, while mtIF3 is speculated to coordinate the initiation process by ensuring that mRNA first binds to mtSSU. In the elongation phase, mtEFTu facilitates the delivery of aminoacylated tRNA to the ribosome by hydrolyzing GTP. After delivery, mtEFTu replenishes GTP and binds to the next aminoacylated tRNA under the influence of mtEFTs. During elongation, mtEFG1 catalyzes mRNA‒tRNA translocation by hydrolyzing GTP. Furthermore, mtEF4 enables reverse mRNA‒tRNA translocation by hydrolyzing GTP, which allows for error correction during protein synthesis. When translation errors occur, C12ORF65 and MTRES1 work in concert to rescue stalled ribosomes by releasing nascent chains and tRNAs. ICT1 is likely involved in the process of releasing the nascent peptide chain. The termination of the translation process is dominated by mtRF1a, which reads the stop codon and possesses peptidyl tRNA hydrolase (PTH) activity. Following the release of the nascent peptide chain, the mitochondrial ribosome recycling factors mtRRF2 and mtEFG2 collaborate to dissociate ribosomal subunits for subsequent translation. Under stress conditions, GTPBP6 provides an additional pathway for ribosomal subunit dissociation

Fig. 2

Physiological consequences of the inhibition of mitochondrial translation Mitochondrial translation can directly initiate the mitochondrial stress response, which in turn leads to the significant inhibition of cytoplasmic translation, thereby affecting cell function through signaling pathways such as the ISR (integrated stress response) and mTOR (mechanistic target of rapamycin). A key feature of mitochondrial translation inhibition is the impairment of OXPHOS function. Studies have shown that the inhibition of OXPHOS can result in an insufficient energy supply for multiple cell types, thereby inhibiting their proliferation and growth. An impairment of OXPHOS also induces changes in the abundances of metabolites, including acetyl coenzyme A. Many of these metabolites are involved in regulating epigenetic features. Alterations in their abundances can lead to epigenetic modifications dominated by histone acetylation and DNA methylation, potentially influencing cell differentiation and function. Furthermore, research has revealed that metabolic enzymes with RNA-binding capabilities, also known as “moonlighting” phenomena, may affect the expression of T-cell-associated effectors. These secondary effects of metabolic enzymes are likely linked to aberrant OXPHOS function

Fig. 3

Correlations between mitochondrial and cytoplasmic translation Mitochondrial translation is interconnected with cytoplasmic translation through a series of stress response pathways. Under mitochondrial stress, mitochondria release DELE, which binds to HRI, an eIF2α kinase, leading to the phosphorylation of the translation initiation factor eIF2α. Another eIF2α kinase, GCN2, is also speculated to be involved in this process. Phosphorylation of eIF2α triggers widespread translational repression in the cytoplasm and the selective translation of mRNAs containing upstream open reading frames (uORFs), including ATF4, ATF5, and CHOP. When misfolded proteins accumulate in the mitochondrial matrix, cells activate a homeostatic protein control system known as the mitochondrial unfolded protein response (mtUPR). In mammals, ATF5 has been identified as a transcription factor that mediates the mtUPR. ATF5 possesses both a nuclear localization sequence (NLS) and a mitochondrial targeting sequence (MLS). In the event of mitochondrial damage, ATF5 translocates to the nucleus and cooperates with ATF4, CHOP, and other transcription factors to activate the mtUPR. The mtUPR induces the expression of HSPs, LONP1, CLPP, and other nuclear-encoded mitochondrial chaperone proteins and proteases to restore mitochondrial function. It also directly reduces mitochondrial translation by downregulating and degrading the RNase P subunit MRPP3. Furthermore, to alleviate mitochondrial stress, the translation and import of nuclear-encoded OXPHOS subunits and mitochondrial proteins are inhibited. Under physiological conditions, mTORC1 promotes cytoplasmic translation by activating S6K and preventing the binding of 4EBP to eIF4E. However, during mitochondrial stress, the induction of cytoplasmic translation is hindered

Fig. 4

Mitochondrial translation in normal hematopoiesis Hematopoiesis is the process by which hematopoietic stem cells (HSCs) differentiate into various types of mature blood cells. According to the classical hematopoietic hierarchy model, HSCs first differentiate into multipotent progenitor cells (MPPs). MPPs can follow two differentiation pathways: One leads to the lymphoid lineage, forming common lymphoid progenitors (CLPs), which further differentiate into mature blood cells, including T cells, B cells, and NK cells. The second pathway leads to the myeloid lineage, forming common myeloid progenitors (CMPs). CMPs can differentiate into megakaryocyte/erythroid progenitors (MEPs) and granulocyte/macrophage progenitors (GMPs). MEPs further differentiate into mature blood cells, such as macrophages, platelets, and erythrocytes, whereas GMPs differentiate into neutrophils, basophils, eosinophils, and macrophages. Based on current research, we annotated the cellular processes influenced by mitochondrial translation in different cells, as detailed in the main text. Importantly, certain blood cells, such as NK cells and granulocytes, which have not been fully studied, are not depicted in this figure

Fig. 5

Current methods for studying mitochondrial translation (a) Fluorescence noncanonical amino acid tagging in mitochondria (mito-FUNCAT) allows the incorporation of bioorthogonal amino acids containing click-responsive alkynes or azides into newly synthesized mitochondrial proteins in the presence of cytoplasmic translational inhibition. Mitochondrial translation is subsequently assessed by on-gel detection, in situ microscopy or FACS. (b) Mitochondrial ribosome profiling (Mito Ribo-seq). Mammalian mitochondrial ribosomes are separated by size from cellular ribosomes by sucrose density gradient ultracentrifugation after RNase treatment, and mRNA fragments protected by mitochondrial ribosomes are analyzed using in-depth sequencing. (c) The addition of a mixture of recombinant mitochondrial factors, 55 S mitochondrial ribosomes, and tRNA to a single reaction allows the synthesis of mitochondrial and model proteins from leaderless mRNAs in a cell-free environment. (d) Morpholino–Jac1 chimeras can be introduced into purified mitochondria for mRNA-specific translational silencing via the TOM/TIM23 complex