Targeted mRNA degradation by complex-mediated delivery of antisense RNAs to intracellular human mitochondria.
Mitochondrial dysfunction underlies a large number of acute or progressive diseases, as well as aging. However, proposed therapies for mitochondrial mutations suffer from poor transformation of mitochondria with exogenous DNA, or lack of functionality of the transferred nucleic acid within the organelle. We show that a transfer RNA import complex (RIC) from the parasitic protozoon Leishmania tropica rapidly and efficiently delivered signal-tagged antisense (STAS) RNA or DNA to mitochondria of cultured human cells. STAS-induced specific degradation of the targeted mitochondrial mRNA, with downstream effects on respiration. These results reveal the existence of a novel small RNA-mediated mRNA degradation pathway in mammalian mitochondria, and suggest that RIC-mediated delivery could be used to target therapeutic RNAs to the organelle within intact cells.
Mukherjee
Saikat
S
Genetic Engineering Laboratory, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Calcutta 700032, India.
Mahata
Bidesh
B
Mahato
Biraj
B
Adhya
Samit
S
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019069:Cell Respiration; D018390:Gene Targeting; D006801:Humans; D007895:Leishmania tropica / Q000235:genetics; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D034443:RNA Transport; D016372:RNA, Antisense / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D016053:RNA, Protozoan / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D012365:RNA, Transfer, Tyr / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology
D024101:Mitochondrial Proteins; D016372:RNA, Antisense; D016053:RNA, Protozoan; D012365:RNA, Transfer, Tyr