Abstract
Mitochondrial metabolism, dynamics, and stress responses in the intestinal stem cell niche play a pivotal role in regulating intestinal epithelial cell homeostasis, including self-renewal and differentiation. In addition, mitochondria are increasingly recognized for their involvement in sensing the metabolic environment and their capability of integrating host and microbial-derived signals. Gastrointestinal diseases such as inflammatory bowel diseases and colorectal cancer are characterized by alterations of intestinal stemness, the microbial milieu, and mitochondrial metabolism. Thus, mitochondrial function emerges at the interface of determining health and disease, and failure to adapt mitochondrial function to environmental cues potentially results in aberrant tissue responses. A mechanistic understanding of the underlying role of mitochondrial fitness in intestinal pathologies is still in its infancy, and therapies targeting mitochondrial (dys)function are currently lacking. This review discusses mitochondrial signaling and metabolism in intestinal stem cells and Paneth cells as critical junction translating host- and microbe-derived signals into epithelial responses. Consequently, we propose mitochondrial fitness as a hallmark for intestinal epithelial cell plasticity, determining the regenerative capacity of the epithelium.
Highlights
Intestinal epithelial cells (IECs) are crucial for digestive processes and form a physical and immune barrier for host defense (Peterson and Artis, 2014)
We briefly describe the role of the mitochondrial function in intestinal stem cell (ISC) niche homeostasis and summarize the current knowledge of external and internal signals converging on the mitochondrial function to control epithelial responses in health and disease
These data suggest that mitochondrial dysfunction and the associated aberrant phenotype of Paneth cells (PCs) and ISCs are an early event in Crohn’s disease (CD) pathology; further research is needed to clarify if these alterations are initiating events or already compensatory responses to maintain tissue homeostasis
Summary
Intestinal epithelial cells (IECs) are crucial for digestive processes and form a physical and immune barrier for host defense (Peterson and Artis, 2014). Besides actively cycling ISCs, a population of slow-cycling ISCs, termed according to their position as + 4 ISCs or reserve ISCs, is located above the crypt base and is characterized by the expression of maker genes including Hopx, Lrig, Tert, and Bmi (Sangiorgi and Capecchi, 2008; Montgomery et al, 2011; Takeda et al, 2011; Powell et al, 2012) These cells are resistant against acute, genotoxic stress and replace damaged CBCs in response to injury, ensuring tissue regeneration (Montgomery et al, 2011; Wang et al, 2019). EXTRINSIC AND INTRINSIC SIGNALS AFFECTING MITOCHONDRIAL FUNCTION IN THE ISC NICHE
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