Mitochondrial Metabolism in the Intestinal Stem Cell Niche—Sensing and Signaling in Health and Disease

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.

Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury

“…Injury-associated stem cells are imperative in orchestrating tissue regeneration, and dynamic adaptations of mitochondrial metabolism in the intestinal stem cell (ISC) niche are essential to ensure tissue homeostasis. Thus, these results support the concept in which a reduced metabolic flexibility of IECs affects the regenerative capacity of the epithelium and renders the intestinal mucosa towards increased susceptibility to inflammatory triggers 8 . Mitochondria are increasingly recognized as site of microbial signal-integration, and microbiome-derived metabolic signals emerge as an important player in determining the ability for mucosal healing 9 – 11 .…”

“…In the inflamed tissue microenvironment of IBD patients, infiltrating immune cells, together with the energy requirements of resident epithelial and stroma cells limit the available oxygen 14 , and together with a reduced blood supply, these changes contribute to hypoxic conditions in chronic inflammation 15 . Interestingly, mitochondrial dysfunction and associated changes in intestinal epithelial functions are suggested as early event in the pathogenesis of IBD, preceding inflammatory tissue aberrations 8 , 16 – 21 . In particular, impaired mitochondrial function in intestinal epithelial cells (IEC) is associated with reduced stemness and Paneth cell dysfunction 18 , 20 , 22 .…”

Long-Term Caffeine Intake Exerts Protective Effects on Intestinal Aging by Regulating Vitellogenesis and Mitochondrial Function in an Aged Caenorhabditis Elegans Model

“…Mitochondrial alterations lead to a decline in energy production at the cellular level, which is associated with aging, as shown in animal models as well as human tissues [ 45 , 59 , 60 , 61 , 62 ]. The human colon is markedly affected by the progression of mitochondrial aging, which has emerged as an important player in intestinal tissue homeostasis and pathogenesis [ 63 ]. An association between aging human colonic cells and defective complexes of the respiratory chain has also been described [ 59 ].…”

Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

“…Mitochondrial dysfunction combined with the release of mitochondrial damage-associated molecular patterns (mt-DAMP) is key to HSC activation and liver fibrosis [ 8 ]. On the other hand, mitochondrial quality control mechanisms, including mitochondrial unfolded protein response (UPR mt ), dynamics, and mitophagy, are central to maintaining mitochondrial homeostasis [ 9 , 10 ]. UPR mt constitutes mito-nuclear communication of stress signals derived from mitochondria-promoting transcriptional activity in the nucleus that generates mitochondrial chaperones (e.g., heat shock protein 10, 60, and 90 (HSP10, 60, and 90)) and proteases for repairing unfolded protein stress [ 11 ].…”