Researchers Explore Potential Treatment for Mitochondrial Diseases

UConn researchers are studying a group of compounds that could protect mitochondria in ways that might prevent devastating illnesses like muscular dystrophy and ALS.

Huntington’s. Parkinson’s. Muscular dystrophy. Lou Gehrig’s. These diseases share a common cause that devastatingly robs sufferers of their energy, muscle control, and in the case of Huntington’s, their sanity. But now, a group of researchers from UConn describes how a possible therapy might work.

What all those fearsome diseases have in common is dysfunctional mitochondria. Mitochondria are the body’s tiny power plants. These minuscule, rod-shaped structures inside our cells take in oxygen and nutrients and put out ATP, the body’s fuel (ATP is to cells what gasoline is to cars.) When mitochondria don’t work so well, the dysfunction can cause strange and awful symptoms that are particularly distressing in parts of the body that require lots of energy: particularly muscles, the brain, and nerve tissue.

Mitochondrial diseases tend to worsen with age. Scientists have guessed that mitochondria age as the rest of our body does. Damage acquired over time may contribute to mitochondrial diseases, but they aren’t entirely sure what’s happening or how to stop it.

“They’re insidious diseases because they rob your cells of their energy. They’re so hard to diagnose and the symptoms can be so diverse,” says Nathan Alder, a molecular biophysicist in the Department of Molecular and Cell Biology at UConn.

Alder and other researchers from UConn, the University of Texas, and Alexandria LaunchLabs are researching a group of compounds that seem to protect and even repair damage to mitochondria. The researchers describe the compounds, called SS peptides, and one potential way they may work to heal mitochondria in an upcoming issue of the Journal of Biological Chemistry.

SS peptides are made of amino acids, the building blocks of proteins, but each SS peptide is only four amino acids long. They all have the same basic plan: two amino acids with a positive charge alternating with two aromatic amino acids (“aromatic” is a chemistry term meaning they have a ring-like structure similar to benzene).

Previous research by Hazel Szeto at Cornell University, who first described SS peptides and served as co-author on this study, showed that SS peptides can enter into any cell in the body, and mitochondria suck them up like sponges. Alder and his colleagues wanted to figure out what the peptides were doing when they got in there. Using approaches ranging from computer modeling to studying mitochondria in the lab, they began to see the peptides’ effects. It looks like they can alter and potentially repair mitochondria by tuning the electric properties of their membranes.

Mitochondrial membranes are intricately creviced double-layers of fatty molecules called lipids that surround proteins sticking out of the membrane itself. The outer layer of the membrane “talks” to the rest of the cell, sensing conditions and passing ATP and other molecules back and forth. The labyrinthine inner layer of the membrane holds the ATP factories. One of the special lipids enriched in the inner membrane, cardiolipin, has a strong affinity for SS peptides.

Mitochondria tend to accumulate positively charged things like calcium ions—mitochondria actually serve as storage centers for cellular calcium. Yet calcium overload can cause damage to mitochondria’s cardiolipin-containing membranes over time, ripping into the membrane and causing permanent damage.

SS peptides can prevent that from happening, Alder and his colleagues found. The peptides are positively charged but in a gentler way than calcium; they snuggle up against the mitochondrial membrane and shield it from the smaller, more damaging calcium ions.

“This is probably not the only effect of SS peptides. But it’s an interesting one,” Alder says. The researchers want to understand more about how the peptides interact with the mitochondria and why they appear to have such broad-based efficacy against so many mitochondrial disorders. The team is currently using UConn’s nuclear magnetic resonance facilities to get detailed pictures of SS peptide structural features and how the peptides might alter or maintain the shape of the mitochondrial membranes. “We know they work. We want to know how they work. By understanding the mechanism of action, we can engineer more effective peptide analogs and possibly tailor them to treat specific mitochondrial afflictions,” Alder says.

Article in UConn Today

The following MCB Undergraduate students received 2020 Summer Undergraduate Research Fund awards in support of their summer undergraduate research projects. All SURF projects will be pursued remotely this summer in accordance with restrictions on undergraduate research due to COVID-19. Please note that the project titles listed reflect the original projects proposed.

Akriti Bhattarai '21 (Molecular and Cell Biology, CLAS) Project Title: Identification of Putative Resistance Genes in the Sugar Pine Genome (Pinus lambertiana) and across the White Pines Faculty Mentor: Dr. Jill Wegrzyn, Ecology and Evolutionary Biology

Rei Bufi '21 (Molecular and Cell Biology, CLAS; Individualized Major: Globalization, Art, and Activism, CLAS) Project Title: The Need for Evidence-Based Exercise Intervention for Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis Faculty Mentor: Dr. Linda Pescatello, Kinesiology

Daniel Fairchild '21 (Structural Biology and Biophysics, CLAS; Molecular and Cell Biology, CLAS) Project Title: Near IR Tethered Bichromophoric Fluorophore-Quencher Voltage Sensitive Dye Faculty Mentor: Dr. Ping Yan, Center for Cell Analysis and Modeling

Elena Haarer '21 (Molecular and Cell Biology, CLAS) Project Title: Defining the Functions of the Actin Cytoskeleton in Cellular Senescence and Biological Aging Faculty Mentor: Dr. Kenneth Campellone, Molecular and Cell Biology

Sarah Kricheff, Dec. '20 (Molecular and Cell Biology, CLAS) Project Title: Developing a Biosensor for Mechanical Tension in Live Cells Faculty Mentor: Dr. Yi Wu, Genetics and Genome Sciences

Katherine Lee '22 (Structural Biology and Biophysics, CLAS) Project Title: Computational Investigations into Allostery and Binding Dynamics of Tau Protein Antibodies: Affinity, Specificity and the Potential for Intentional Design Faculty Mentor: Dr. Eric May, Molecular and Cell Biology

Roshni Mehta '22 (Molecular and Cell Biology, CLAS; French, CLAS) Project Title: Who Let the DoGs Out? An Analysis of RNA Transcription Readthrough and Termination Faculty Mentor: Dr. Leighton Core, Molecular and Cell Biology

Jayla Millender '21 (Molecular and Cell Biology, CLAS; Africana Studies, CLAS) Project Title: The Impact of Angiogenic and Osteogenic Factors in the Presence of Biodegradable Piezoelectric Films In Vitro Faculty Mentor: Dr. Thanh Nguyen, Mechanical Engineering

Seema Patel '22 (Molecular and Cell Biology, CLAS) Project Title: TLS Inhibitors: A Promising Class of Compounds as Anti-Cancer Agents Faculty Mentor: Dr. Kyle Hadden, Pharmaceutical Sciences

Ariana Rojas '21 (Molecular and Cell Biology, CLAS) Project Title: The Role of Taxi, Miniature, and an Uncharacterized Homeobox Gene in the Development of Double-Layered Epithelium in Oncopeltus fasciatus Faculty Mentor: Dr. Elizabeth Jockusch, Ecology and Evolutionary Biology

Shannel Senior '22 (Molecular and Cell Biology, CLAS) Project Title: Synthesis and Characterization of Antimicrobial Cyclic Peptides Faculty Mentor: Dr. Alfredo Angeles-Boza, Chemistry

Sameena Shah '21 (Molecular and Cell Biology, CLAS) Project Title: Discriminatory Bullying of Ethnic and Immigrant Minority Youth: Does Cultural and Familial Belongingness Moderate the Relation Between Being Bullied and the Negative Psychological and Behavioral Consequences Faculty Mentor: Dr. Alaina Brenick, Human Development and Family Sciences

Hannah Smith '21 (Molecular and Cell Biology, CLAS) Project Title: Developing an Effective Barcoding Method for Salp Species Differentiation and Phylogenetic Resolution Faculty Mentor: Dr. Rachel O'Neill, Molecular and Cell Biology

Congratulations, SURF awardees!

Dr. Gogarten has been selected as one of this year’s recipients of the faculty Mentorship Excellence Award, in recognition of his outstanding mentorship of undergraduate researchers. He was selected from a very strong group of nominees by a committee of Peer Research Ambassadors in the Office of Undergraduate Research. The undergraduate mentee who nominated him cited his "extraordinary commitment to challenging and supporting them, which transformed their undergraduate experience, fostered their graduate school aspirations, and allowed them to achieve things they never thought possible."  Awards will be presented at the Fall Frontiers in Undergraduate Research Poster Exhibition.

1. MCB 5670-02 Theory and Practice of Laboratory Techniques in Microbiology – Bacterial DNA & RNA Isolation and Quality Control

2. MCB 5671-02 Advanced Theory and Practice of Laboratory Techniques in Microbiology – Characterization of Microbial Communities by 16S rRNA gene sequencing

Faculty Fulbright Scholars Explore Diabetes, Social Media, and Communication
See article in UConn Today

Rachel J. O’Neill, Institute for Systems Genomics, Molecular & Cellular Biology, Genetics and Genome Sciences, College of Liberal Arts and Sciences to be inducted into the Connecticut Academy of Science and Engineering (CASE) for 2020.