Shedding Light on the Role of Mitochondria in Inclusion Body Myositis

Elie Naddaf, MD, a neurologist at Mayo Clinic in Rochester, MN, investigates how mitochondrial dysfunction contributes to IBM and what it reveals about sex-specific differences. His research began with an ANF Development Grant in 2021, which provided essential seed funding. “The first step is always the hardest,” reflects Dr. Naddaf, “especially as a clinician embarking on a translational research journey. The ANF grant provided the needed seed funding to get my research going.”

Dr. Naddaf aims to describe the exact nature of mitochondrial dysfunction in IBM. “The mitochondria play a multifaceted role extending beyond energy production, as they are vital signaling organelles that regulate cellular metabolism and influence cell fate,” he explains. His research utilizes extensive testing and innovative technologies to determine the nature and extent of mitochondrial dysfunction in IBM, while highlighting sex-specific differences. 

Advancements in aging research and the surge of mitochondria-targeted therapies at different stages of development, inspired Dr. Naddaf’s research. “By reframing IBM as a disease of aging, we aim to identify the mechanisms it shares with other aging-related disorders. Doing so would allow any therapeutic breakthroughs in the broader field of aging to be applied to IBM and would expand the arsenal of investigational drugs to be considered in IBM.” He hopes along with these results; the research will explain the complicated disease pathogenesis and why males are at a higher risk of IBM.  

A field as complex as neurodegeneration and aging is expansive and intricate and, as Dr. Naddaf notes, requires a methodical, step-by-step approach to fully understand its complexities. Yet, regardless of the specific area they study, he says it has been evident that IBM shares critical similarities with these conditions. “There are pathways, originally intended to be protective, that become aberrantly activated and form self-sustaining vicious cycles that are detrimental to the cell. To develop breakthrough therapies, it is crucial to understand how and when to intervene on these intertwined pathways.” 

He has also observed striking differences in IBM pathomechanisms between males and females across all experiments. “This is a topic that has not been addressed to date despite the disease being known to affect males more commonly and, perhaps, more severely.”  

Following Dr. Naddaf’s ANF research grant, he received a K08 career development grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). He published two projects so far supported by these grants, one focusing on the altered mitophagy and inflammasome activation in IBM, and one provided a detailed metabolomic map of IBM centered on the mitochondria. Both projects presented the results by sex and aimed to determine the clinical significance of the findings.

Now nearing the end of the K08 grant, he is preparing to transition into independent investigation, where he plans to build on his discoveries from the ANF and NIAMS grants. “Our knowledge about mitochondrial dysfunction in IBM has largely been limited to investigating mitochondrial DNA mutations in muscle tissue. Exploring the different aspects of mitochondrial biology and behaviors in IBM could enhance our understanding of disease mechanisms and pave the way for novel therapeutic interventions.” 

Dr. Naddaf reflects on the support he received through grants and highlights their impact on NM medicine and patients with NM diseases. “Funding research is of utmost importance. The main goal is to make an impact on patients’ lives by improving or curing their conditions. To achieve that, we must invest in research at all stages to facilitate translation from bench to bedside.” 

Learn more about ANF research grants, and how you can help support research efforts like this today.