The aftermath of being CLUHless in the colon

Lekha Bandopadhyay

Mitochondrial dysfunction and inflammation in patients with ulcerative colitis (UC) have been linked by a recent study led by Amit Lahiri, a Senior Scientist at CSIR-Central Drug Research Institute, Lucknow. The study identified the protein CLUH as a regulator of mitochondrial dysfunction and inflammation, providing insights into potential druggable targets for UC treatment.

Pictorial representation of the result of depletion of CLUH in macrophages and biopsy samples collected from UC patient's colon compared to healthy individuals. Photo credit: Khan et al., 2023
Pictorial representation of the result of depletion of CLUH in macrophages and biopsy samples collected from UC patient's colon compared to healthy individuals. Photo credit: Khan et al., 2023 

With great power comes great responsibility. In the cellular world, this adage is apt for mitochondria, which are not only the cellular powerhouses but also have a central position in cellular processes. Mitochondrial dysfunction undoubtedly holds clues to many chronic diseases.

Amit Lahiri, Senior Scientist, CSIR-Central Drug Research Institute (CDRI), Lucknow, studies the pathogenesis of inflammatory bowel disease (IBD). He notes Ulcerative Colitis (UC), one arm of IBD, is a chronic disorder which affects the lives of millions. The number of patients suffering from this condition has been increasing globally, including that in the Indian population. Mitochondrial dysfunction has been documented in UC patients without any well-defined cause by clinical researchers.” 

Lahiri says, We wanted to understand the connection between mitochondrial dysfunction and the heightened immune response observed in UC patients with an aim to identify new druggable targets.” CLUH (Clustered mitochondria protein homolog), a cellular protein, crucial for the survival of newborn animals, is known to regulate mitochondrial metabolism and intracellular distribution. A team of researchers led by Lahiri recently reported that CLUH regulates mitochondrial dysfunction and inflammation in UC patients. 

Initially, they noted reduced expression of CLUH in affected tissues from UC patients compared to healthy ones. An extensive analysis was done with human colon tissue, and intestinal macrophages (immune cells), which revealed that reduced CLUH level in the human colon lead to increased mitochondrial fragmentation, reduced mitophagy (clearance of fragmented or dysfunctional mitochondria), increased secretion of cytokines (proteins regulating inflammation), and a consequent spike in inflammation in UC patients. 

They further found that, in both healthy tissues and macrophages, CLUH, as a master regulator, allows mitophagy and thus checks the inflammation by suppressing dynamin related protein 1 involved in mitochondrial fragmentation and secretion of cytokines. Further analysis on roundworms and mice in response to stimulators mimicking UC conditions confirmed the above observations. 

Mitochondrial biologist Ullas Kolthur, Professor, Tata Institute of Fundamental Research, Mumbai, discovered, in a collaborative study, how brain cells protect themselves by regulating the number and functions of mitochondria. He comments, Mitochondria have emerged as key determinants of macrophage function and in this regard, the current study has provided a novel mechanistic understanding of how mitochondrial dysfunction contributes to UC.” 

Kolthur thinks it is exciting to see how bacterial/​pathogenic components remodel mitochondria and affect mitophagy in cells like macrophages, which often form the first line of defense. He adds, While this reiterates the importance of mitochondria in infection and inflammation, investigating whether this mechanism is operative in other tissues or contexts will be key in the future.”

Radha Rangarajan, Director, CSIR-CDRI also thinks that investigation of CLUH’ or other mitochondrial proteins as diagnostic markers can be a fruitful avenue of future research in UC and other diseases. Rangarajan further says We will check in the future if there is cross-talk between mitochondrial dysfunction and gut bacterial dysbiosis in the UC patients.” 

Lahiri shared his experience as a Young Investigator here in 2020, and incidentally, this is the first major discovery from his group. The maximum work of this study was done by his graduate student Shaziya Khan, and this is a part of her PhD thesis. Lahiri notes that I try to select passionate students with an inherent interest in science, who have the enthusiasm and excitement to run the experiments.”

Lahiri with his graduate student Shaziya Khan, the first author of the study
Lahiri with his graduate student Shaziya Khan, the first author of the study

During the study, Lahiri established strong collaborations with other scientists in CSIR-CDRI as well as clinical scientists Tulika Chandra, Professor, Kings George Medical University, Lucknow, and Uday C. Ghoshal, Professor, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. He says, The collaborations have been instrumental in carrying out the work. These were also critical in getting the clinical research done using all primary human cells and biopsy samples, as initially, it was difficult to collect human macrophages and IBD colon tissue samples.”