NLRX1 resides in mitochondrial RNA granules and regulates mitochondrial RNA processing and bioenergetic adaptation.

The role of mitochondria is emerging in regulation of innate immunity, inflammation and cell death beyond its primary role in energy metabolism. Mitochondria act as molecular platform for immune adaptor protein complexes, which participate in innate immune signaling. The mitochondrial localized immune adaptors are widely expressed in non-immune cells, however their role in regulation of mitochondrial function and metabolic adaption is not well understood. NLRX1, a member of NOD family receptor proteins, localizes to mitochondria and is a negative regulator of anti-viral signaling. However, the submitochondrial localization of NLRX1 and its implication in regulation of mitochondrial functions remains elusive. Here, we confirm that NLRX1 translocates to mitochondrial matrix and associates with mitochondrial FASTKD5 (Fas-activated serine-threonine kinase family protein-5), a bonafide component of mitochondrial RNA granules (MRGs). The association of NLRX1 with FASTKD5 negatively regulates the processing of mitochondrial genome encoded transcripts for key components of complex-I and complex-IV, to modulate its activity and supercomplexes formation. The evidences, here, suggest an important role of NLRX1 in regulating the post-transcriptional processing of mitochondrial RNA, which may have an important implication in bioenergetic adaptation during metabolic stress, oncogenic transformation and innate immunity.