A deeply conserved miR-1 dependent regulon supports muscle cell physiology

Abstract

Muscles are not only essential for force generation but are also key regulators of systemic energy homeostasis1. Both these roles rely heavily on mitochondria and lysosome function as providers of energy and building blocks, but also as metabolic sensors2-4. Perturbations in these organelles or their crosstalk lead to a wide range of pathologies5. Here, we uncover a deeply conserved regulon of mitochondria and lysosome homeostasis under control of the muscle-specific microRNA miR-1. Animals lacking miR-1 display a diverse range of muscle cell defects that have been attributed to numerous different targets6. Guided by the striking conservation of miR-1 and some of its predicted targets, we identified a set of direct targets that can explain the pleiotropic function of miR-1. miR-1-mediated repression of multiple subunits of the vacuolar ATPase (V-ATPase) complex, a key player in the acidification of internal compartments and a hub for metabolic signaling7,8, and of DCT-1/BNIP3, a mitochondrial protein involved in mitophagy and apoptosis9,10, accounts for the function of this miRNA in C. elegans. Surprisingly, although multiple V-ATPase subunits are upregulated in the absence of miR-1, this causes a loss-of-function of V-ATPase due to altered levels or stoichiometry, which negatively impact complex assembly. Finally, we demonstrate the conservation of the functional relationship between miR-1 and the V-ATPase complex in Drosophila.

Metabolic decisions in development and disease—a Keystone Symposia report

“…Gutiérrez‐Pérez showed that the main and conserved role of miR‐1 is to control several subunits of the V‐ATPase complex, which is ultimately essential to guarantee the assembly of this intricate complex in muscle cells. These results reveal a novel role for this microRNA in regulating protein complex assembly, and highlight the importance of mitochondrial function and proteostasis in muscle physiology 81 …”

Two MicroRNAs Are Sufficient for Embryonic Patterning in C. elegans

“…In contrast in C. elegans , most miRNAs are not required for viability in the lab, even at later stages [ 25 ]. This distinction between worms and mice likely reflects a difference in the tolerance of each organism to defects in the production of differentiated cells rather than generally distinct roles of miRNAs (e.g., miR-1-deficient C. elegans also show a range of molecular and cellular defects in muscles, but the animals are still fully viable in the lab) [ 50 , 51 , 52 ].…”

A pan-cnidarian microRNA is an ancient biogenesis regulator of stinging cells

“…Precision of gene expression output is often difficult to control using transcription factors alone because transcription is an inherently noisy process 47 . Therefore, complex biological processes that govern development and cell differentiation in bilaterians recruited miRNA regulation to tune levels of dosage sensitive genes involved in these processes [48][49][50] . Two kinds of such miRNA-target modes of regulation are known: (1) coherent and (2) incoherent 51 .…”