Our laboratory is interested in how mitochondria communicate and regulate biological processes at the cellular and organismal level. We currently focus largely on bioactive peptides that are encoded in the mitochondrial genome that mediate mitochondrial regulation to maintain metabolic homeostasis.
Mitochondria are ancient organelles that are thought to have originated from free-living bacteria. They significantly upgraded our ability to extract energy from carbon sources, allowing a more complex system to exist. Today, mitochondria act as major coordinators of our complex metabolic system. All coordination requires some form of communication, and our lab is interested in how mitochondria have evolved to dynamically communicate to the cell, such that not only did they come to coordinate a complex metabolic system, but also actively regulate metabolic changes during aging and age-related diseases. Simply put, what were the alphabets of the mitochondrial language that were encoded in the original symbiotic bacterial (proto-mitochondrial) genome, what do they look like today, what are their functions, and how can they help us age better?
To date, a relatively limited number of retrograde signaling molecules and signaling cascades have been explored. Some of the molecules described in this regard are cytochrome C, reactive oxygen species (ROS), Ca2+, Fe2+, nitric oxide (NO), and carbon monoxide (CO). Also, mitochondrial damage can release (i) matrix protein fragments generated by proteolysis that are encoded in the nuclear genome and (ii) mitochondrial DNA (mtDNA) that can activate cellular stress responses. However, as important as these signals are, they are not inherently encoded in mtDNA.
The emerging biology of mitochondrial-derived peptides (MDPs), which collectively refer to short open reading frames (sORFs) encoded in mtDNA that yield bioactive peptides, adds a previously unknown layer of mitochondrial communication. Because they are encoded in the mitochondrial genome, MDPs can be thought to have diverged from a primordial bacterial communication system. Humanin was the first MDP to be identified from a cDNA library created from the surviving fraction of an Alzheimer’s disease (AD) patient brain. Humanin protects neuronal cells from AD-related insults and other age-related insults, including oxidative stress.
We identified a novel sORF encoded in mtDNA and named it MOTS-c based on its genomic location (Mitochondrial ORF within the Twelve S rRNA type c). MOTS-c is the second published MDP. MOTS-c targets the skeletal muscle and promotes cellular glucose and fatty acid metabolism. Within the cell, MOTS-c blocks part of the folate cycle and the tethered de novo purine synthesis at the level of AICAR, causing it to accumulate in the cell. AICAR is a potent activator of AMPK, which partially mediates the metabolic effects of MOTS-c. In mice, MOTS-c regulates glucose homeostasis and prevents obesity and insulin-resistance in high-fat fed young mice. Furthermore, (i) MOTS-c levels in mice decline with age in circulation and skeletal muscle concomitantly with the development of muscle insulin-resistance and (ii) systemic injection of MOTS-c for a week sufficiently reversed age-dependent muscle insulin resistance, suggesting a role in aging biology.
We study MOTS-c at the (i) genetic, (ii) molecular and cellular, and (iii) physiological level to better understand how it is involved in aging and age-related diseases, using multidisciplinary approaches including molecular biology/genetics, proteomics, metabolomics, and various mouse models.
Mitonuclear Communication: Integration at the Genetic Level
It is likely that the endosymbiotic proto-mitochondrial bacteria used peptides encoded in its genome to communicate with our ancestral cells, which is a communication system that is still used by bacteria. It is plausible that the two genomes co-evolved to cross-regulate each other to coordinate cellular functions. Mitochondria-to-nucleus (retrograde) communication mechanisms that respond to cellular stress, including UPRmt and damage-associated molecular patterns (DAMPs), have been well-described, yet, are known to be mediated by nuclear-encoded proteins/peptides. To date, factors encoded in the mitochondrial genome that directly regulate the nuclear genome are unknown. We have identified a peptide encoded in the mitochondrial genome that (i) actively translocates into the nucleus in coordination with nuclear-encoded AMPK in response to metabolic stress and (ii) directly regulates ARE-containing target genes in the nuclear genome, in part, by interacting with NRF2.
In line with the increasing interest on mitonuclear communication in aging, the role of MOTS-c as a mitochondrial-encoded regulator of the nuclear genome may have implications in organismal aging. MOTS-c treatment reversed age-dependent skeletal muscle insulin resistance in mice. Further work on the mechanistic details of nuclear genome regulation by MOTS-c are ongoing in our laboratory.
Our Lab's Mitochondria