Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics

Abstract

Alveolar epithelial type II (AETII) cells are important for lung epithelium maintenance and function. We demonstrate that AETII cells from mouse lungs exposed to cigarette smoke (CS) increase the levels of the mitochondria-encoded non-coding RNA, mito-RNA-805, generated by the control region of the mitochondrial genome. The protective effects of mito-ncR-805 are associated with positive regulation of mitochondrial energy metabolism, and respiration. Levels of mito-ncR-805 do not relate to steady-state transcription or replication of the mitochondrial genome. Instead, CS-exposure causes the redistribution of mito-ncR-805 from mitochondria to the nucleus, which correlated with the increased expression of nuclear-encoded genes involved in mitochondrial function. These studies reveal an unrecognized mitochondria stress associated retrograde signaling, and put forward the idea that mito-ncRNA-805 represents a subtype of small non coding RNAs that are regulated in a tissue- or cell-type specific manner to protect cells under physiological stress.

A Synthetic Small RNA Homologous to the D-Loop Transcript of mtDNA Enhances Mitochondrial Bioenergetics

“…Our previous work demonstrated that the amount of mmu-mito-ncR-805 in the nucleus increased almost 10-fold in CSE-exposed cells. This increase coincided with the recovery from stress ( Blumental-Perry et al, 2020 ). An antisense inhibitor of mito-ncR-805, AI805, revealed a positive regulation of a subset of neMITO genes and energy metabolism by mito-ncR-805 ( Blumental-Perry et al, 2020 ).…”

“…This increase coincided with the recovery from stress ( Blumental-Perry et al, 2020 ). An antisense inhibitor of mito-ncR-805, AI805, revealed a positive regulation of a subset of neMITO genes and energy metabolism by mito-ncR-805 ( Blumental-Perry et al, 2020 ). Accordingly, overexpression of a synthetic oligo corresponding to the full-length mmu-mito-ncR-805 (mmu-ncR-805 FL ) increased the expression of a few neMITO genes and had a beneficial impact on the intermediates of the Krebs cycle ( Blumental-Perry et al, 2020 ).…”

“…Line scans were obtained manually from multiple representative regions under each condition (specified in the figure legends). The Line scans were created using straight line and freehand line tools in FIJI software across the regions of interest: through the cytoplasm, through outlines of mito-ncR-805 areas, which were localized by proximity/partial colocalization with mitochondrial marker Tom20 ( Blumental-Perry et al, 2020 ), and through the nucleus. The plot profile tool was used to determine the fluorescence intensities for the red channel along the line scan.…”

“…We recently identified mtDNA-encoded small non-coding RNA, mmu-mito-ncR-805, which is generated from the D-loop of the L strand of the mitochondrial genome. The mmu-mito-ncR-805 is an abundant transcript that is stored in a granular form in the mitochondria under normal homeostasis and acts as a retrograde signal by translocating into the nucleus in certain cell types during the adaptive response to stress ( Blumental-Perry et al, 2020 ). An increase in its nuclear localization correlates with an increase in the intermediates of the Krebs cycle and mitochondrial respiration and in the improved mitochondrial potential and function.…”

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence

“…Despite mitosRNAs exact biogenesis and cellular trafficking are still uncertain (Vendramin et al, 2017), many studies about their possible function were carried out. Of note, mito-ncR-805 has been shown to have a protective effect to cigarette smoke in alveolar epithelial cells, as well as an increased expression of nuclear-encoded genes important for mitochondrial function, supporting the idea that mitosRNAs regulation and function might be cell-type specific (Blumental-Perry et al, 2020).…”