A Mighty Mitochondrial Microprotein: The Protective Role of MOTS-c in Acute Lung Injury

Although mitochondria are crucial metabolic organelles for energy production, they have important roles in cellular and extracellular signaling. Mitochondrial-derived peptides are small, biologically active microproteins shorter than 100–150 amino acids that are encoded by the mitochondrial DNA and can signal throughout the cell (1). The functions of mitochondrial-derived peptides are diverse, having putative roles in nuclear signaling, stress response, cell fate such as apoptosis, energy regulation, and protein translation and translocation. A 16-amino-acid peptide named MOTS-c (gene name: MT-RNR1) described in 2015 has been characterized in the context of aging and metabolic disease, and it features a highly conserved sequence across 14 species, including humans and mice (2). Despite being a small peptide, MOTS-c has shown impressive effects in aging, obesity, and diabetes. In skeletal muscle and fat, MOTS-c improves insulin sensitivity in obesity by regulating the AMPK-folate pathway (2). MOTS-c also enhances health span and exercise capacity in aging (3).

In lung disease, MOTS-c protects against acute lung injury (ALI) associated with myocardial ischemia–reperfusion injury in humans (4) and LPS challenge in mice (5). In the context of ALI, MOTS-c inhibits ferroptosis and reduces oxidative stress pathways in vitro by altering PPAR-γ and MAPK signaling (4, 6). In chronic obstructive pulmonary disease (COPD), MOTS-c is reduced in subjects with stable COPD, compared with smokers with normal lung function (7), and is reduced in plasma during acute exacerbations of COPD (8). Together, these studies support a unique protective role for MOTS-c in the lung.

In this issue of the Journal, Shen and colleagues (pp. 353–368) provide new insights in the lung for the mighty peptide, MOTS-c (9). They report the protective role of MOTS-c in the metabolic reprogramming of pulmonary vascular endothelial cells after lung ischemia–reperfusion injury (LIRI) (9). They demonstrate in a prospective human study that levels of MOTS-c are significantly reduced in subjects who develop ALI because of ischemia–reperfusion injury after cardiopulmonary bypass. Levels of MOTS-c positively correlated with the ratio of arterial oxygen tension or pressure with fraction of inspired oxygen, a marker of severity of ALI. In a rat model of LIRI, pretreatment with MOTS-c prevented lung injury, enhanced glycolysis by preservation of PFKFB3 expression, and reduced markers of ferroptosis (Figure 1). They further show, in vitro, that PFKFB3 is necessary for MOTS-c to promote a metabolic shift to glycolysis, suppressing oxidative stress and ferroptosis in pulmonary vascular endothelial cells in the context of ischemia. This study demonstrates an important connection between MOTS-c and the PFKFB3-AMPK-HIF1 response pathway to ischemic injury. This study makes novel contributions to the field by defining how MOTS-c alters the metabolic program of vascular endothelial cells in addition to promoting beneficial metabolic signaling pathways.

Figure 1.

MOTS-c schematic. Phos. = phosphorylation.

Several key limitations of the study exist. For human subjects, plasma samples were collected only after cardiopulmonary bypass without a paired presurgical sample. All patients with ALI within this study were defined as hyperinflammatory type on the basis of classifications described by Calfee and colleagues (10). This limits the applicability of the findings to other forms of ALI. It does raise important questions: Do reduced levels of MOTS-c at baseline predict development of LIRI? Do MOTS-c plasma levels differ in patients with acute respiratory distress syndrome with hypo- versus hyperinflammatory phenotypes? Important follow-up studies are needed to evaluate MOTS-c levels in a broader context of lung injury. In vitro experiments for this study focused on human pulmonary microvascular endothelial cells. Although these cells may be the primary target in ischemia–reperfusion injury in the lung, the impact of MOTS-c on lung epithelial cells may be very important for lung repair and recovery from ALI.

This study provides additional exciting evidence for the protective role of MOTS-c and a basis for future investigation of its role in lung injury and critical illness. Additional studies to understand the mechanism of action of MOTS-c in other cell types in the lung—including the lung epithelium, fibroblasts, and immune cells—will be essential to help define new therapeutic opportunities for this mighty peptide. Finally, many other mitochondrial microproteins exist with unknown functions in the lung, making this a rich landscape for future investigations in lung disease, and may ignite the discovery of new biomarkers and therapeutic approaches.