The LETM domain: core region for K+ and NAD+/H homeostasis

Mitochondria are small powerhouses within our cells with crucial roles in our body`s functions. When these cellular powerhouses malfunction, it can lead to serious conditions like neurodegenerative diseases. Our focus is on LETM1, a gene implicated in seizures and linked to a complex disorder known as Wolf-Hirschhorn Syndrome (WHS). Recent research has revealed concerning findings: newborns and infants with mutations in both copies of the LETM1 gene face severe symptoms affecting their nervous system, muscles and metabolism, with poor prognoses. So, what does LETM1 do? It`s a regulator of the mitochondrial volume, maintaining the balance of certain cations within mitochondria, crucial for mitochondrial structure and function. When LETM1 is not working properly, mitochondria accumulate K+, swell, and lose their organized structure. This leads to metabolic problems, including reduced energy and difficulty managing important molecules like NAD+ and mitochondrial DNA. Understanding the role of LETM1 is complicated because it seems to affect so many different aspects of cell function. We found that many LETM1 mutations identified in patients fall into a specific region of LETM1 called the LETM domain. By focusing on the LETM domain we hope to uncover its primary function and how it relates to disease. Our research involves studying cells, both normal and those with LETM1 mutations found in patients as well as to analyze the LETM domain in a cell free system to understand how LETM1 works. We are hopeful that discovering new connections between how cells manage mitochondrial K+ and important metabolic molecules levels like NAD+ could lead to new treatments for diseases like WHS.