Mitochondrial translation and respiratory machinery

The mitochondrial translation and respiratory machinery is an integrated system within the mitochondria responsible for synthesizing essential proteins and generating cellular energy through oxidative phosphorylation (OXPHOS) [1, 13]. This machinery comprises the mitochondrial ribosome (mitoribosome), which translates 13 core subunits of the respiratory chain encoded by the mitochondrial genome, and the five multi-subunit complexes (I-V) of the electron transport chain [1, 14]. In various diseases, particularly aggressive and chemoresistant cancers, cells exhibit a heightened dependency on this machinery to meet their bioenergetic and biosynthetic demands [3, 7, 9]. Therapeutic strategies targeting this system include the use of antibiotics like tigecycline to inhibit mitochondrial translation and small molecules like metformin or IACS-010759 to disrupt specific respiratory complexes [2, 6, 10]. These interventions aim to induce metabolic stress, deplete ATP, and trigger apoptosis in cells that are 'addicted' to mitochondrial function [4, 8, 10]. However, because these processes are also vital for normal cell function, targeting this system carries risks of systemic mitochondrial toxicity [2, 13]. Notable side effects include lactic acidosis, organ dysfunction, and peripheral neuropathy, which present significant challenges in clinical development [2, 10]. Despite these challenges, the machinery remains a high-interest target for overcoming drug resistance and treating metabolic vulnerabilities in cancer and infectious diseases [1, 12, 14].

Other names

Mitochondrial protein synthesis machineryMitochondrial oxidative phosphorylation systemOXPHOS machineryMitoribosome and Electron Transport ChainMitochondrial gene expression and bioenergetics system

Inhibition of mitochondrial protein synthesis by binding to the mitoribosome or inhibition of electron transport chain complexes (I-V) to disrupt oxidative phosphorylation and ATP production [1, 2, 10].