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

Anna Blumental‐Perry ,Z.-W Ye,Yaron Perry ,Carl Nelson ,Kusum Pandit ,Harshavardhan Kenche ,Min Kang ,E Prendergas,Dawid Krokowski ,Bo Guan ,Jie Zhang ,Alexander Miron ,Naftali Kaminski ,Susan H Guttentag ,Ilya Bederman ,Phillip Linden ,Raul Jobava ,Farida Ahangari ,Danyelle M Townsend ,Neil Molyneaux ,Jianrong Wu ,A J Degar,Noam Perry ,Maria Hatzoglou

doi:10.1038/s42003-020-01322-4

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.

Highlights

Alveolar epithelial type II (AETII) cells are important for lung epithelium maintenance and function
Principal component analysis of miRNA expression showed that analyzed groups are statistically unique, with the expression pattern at 10 h of CS extract (CSE) exposure more similar to that of the control cells than the 2 h, supporting that 10h CSE exposure corresponds to the recovery phase at the level of known stress-signaling components and miRNA expression (Fig. 1c)
It is upregulated in response to cigarette smoke (CS) exposure during the adaptive phase in AETII cells in a mouse model of chronic obstructive pulmonary disease (COPD) and in primary AETII cells in culture

Summary

Introduction

Alveolar epithelial type II (AETII) cells are important for lung epithelium maintenance and function. CS-exposure causes the redistribution of mito-ncR805 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. Elongated mitochondria can better maintain energy production under stress[22], elongation is a sign of adaptation This resistance suggests of the existence of molecular mechanisms that protect AETII cells from initial CS-induced injury[23]. It is not known whether mitochondrial elongation is the only protective mechanism in AETII cells

Methods

Results

Conclusion