Mitochondrial function and gastrointestinal diseases

Abstract

Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.

Fig. 1 |. Canonical metabolic pathways in a cell.

Glucose metabolism produces lactate through aerobic glycolysis or acetyl-CoA, which enters the tricarboxylic acid cycle (TCA) cycle for oxidative phosphorylation. Intermediate products during glycolysis, such as glucose-6-phosphate, branch off to the pentose phosphate pathway to ultimately participate in nucleotide synthesis (1). Fatty acids get metabolized to fatty acyl-CoA in the cytoplasm, and the addition of carnitine facilitates entry into the mitochondria for fatty acid oxidation (FAO). The end product of FAO, acetyl-CoA, enters into the TCA cycle (2). Glutamine gets converted to glutamate through glutaminolysis in the cytoplasm and enters into the mitochondria to be converted to α-ketoglutarate (α-KG) to support the TCA cycle (3). Different intermediates in the TCA cycle support anabolic reactions necessary for cell survival. Citrate leaves the mitochondria, converts to acetyl-CoA in the cytoplasm and participates in fatty acid synthesis (4). Succinyl-CoA (suc-CoA) and oxaloacetic acid (OAA) are essential building blocks in haem and amino acid synthesis, respectively. Ultimately, the TCA cycle produces electron carriers NADH and FADH₂ molecules, which donate their electrons to the electron transport chain (ETC) for the synthesis of H₂O and ATP. Cyt C, cytochrome c.

Fig. 2 |. Mitochondrial dysfunction in inflammatory bowel diseases.

a, Both ulcerative colitis and Crohn’s disease can present with abdominal pain, diarrhoea and bloody stools. Pathological and molecular features can distinguish ulcerative colitis and Crohn’s disease. Ulcerative colitis affects the rectum and colon and spreads proximally in a continuous fashion with inflammation limited to mucosa or submucosa. Crohn’s disease can affect any part of the gastrointestinal tract, involving the terminal ileum most commonly, with discontinuous, transmural inflammation characterized by a patchy, cobblestone appearance. b, In a healthy colon, intestinal epithelial cells (IECs) display a differential metabolic activity with high mitochondrial respiration and O₂ consumption by oxidative phosphorylation (OxPHOS) at the crypt top, which contributes to a physiological hypoxic microenvironment at the surface epithelial luminal interface. This hypoxic microenvironment promotes healthy commensal obligate anaerobes dominated by Firmicutes (now Bacillota phyla), which facilitate the synthesis of short-chain fatty acids (SCFAs), particularly butyrate, from dietary fibres that fuel IEC OxPHOS, thereby forming a positive feedback loop between host IECs and microbiota. This symbiotic association between IEC and microbiota has a major role in intestinal homeostasis to maintain epithelial barrier function. In inflammatory bowel disease (IBD), impaired IEC mitochondrial function is implicated to include (1) impaired fission and fusion dynamics, (2) damage to mitochondrial proteins, lipids and/or mitochondrial DNA (mtDNA) thereby hindering metabolism and other mitochondrial functions, and (3) insufficient mitophagy to remove the mitochondrial population suffering perpetual or severe damage. This mitochondrial dysfunction is associated with increased mitochondrial reactive oxygen species (mtROS) and release of mtDNA that drive inflammatory responses. Mitochondrial dysfunction in IECs impinges on the physical epithelial barrier, secreted barrier including antimicrobial peptides (AMPs) and mucins, and luminal microbiota composition. Altered IEC mitochondrial energetics (decreased OxPHOS), as can occur during mitochondrial damage, have been implicated in perturbing the metabolic host–microorganism circuit; IECs convert to a more glycolytic metabolism, consuming less O₂ and thereby increasing O₂ bioavailability to the gut microbiota that can promote the expansion of facultative anaerobes, mainly dominated by dysbiotic Proteobacteria. Similarly, in the small intestine (ileum), mitochondrial homeostasis maintains barrier function, IEC renewal and efficient antioxidant machinery that maintain beneficial ROS. Crohn’s disease exhibits mitochondrial dysfunction associated with defective intestinal stem cell (ISC) and Paneth cell function, oxidative stress and microbiota alterations. CRC, colorectal cancer; TA cell, transit-amplifying cell; T_reg cell, regulatory T cell; mtUPR, mitochondrial unfolded protein response.

Fig. 3 |. Mitochondria in different stages of colorectal cancer.

a, In the early stages of colorectal cancer (CRC), downregulation of mitochondrial pyruvate carrier (MPC) in intestinal stem cells (ISCs) prevents pyruvate entry into the mitochondria and inhibits glucose metabolism through oxidative phosphorylation (OxPHOS). This process results in the upregulation of aerobic glycolysis and lactate formation. Mitochondrial metabolism shifts towards oxidation of fatty acids via fatty acid oxidation (FAO) and glutamine. In addition, high-fat diet or obesity triggers FAO in ISCs, and it has a predominant role in driving the initial stages of tumorigenesis. b, Cancer cells in the late stages of CRC metabolize glucose, fatty acids and glutamine through mitochondria depending on nutrient availability and the tumour microenvironment^,. Mitochondrial damage (hypoxia or loss of membrane potential) activates the WNT signalling pathway. WNT activation stimulates mitochondrial biogenesis, increases mitochondrial number and promotes tumour progression. WNT signalling is also activated by mitochondrial FAO; however, there is a lack of studies reporting the direct role of WNT signalling in regulating mitochondrial flexibility in metabolizing glutamine or driving FAO during CRC. The NOTCH pathway activates pro-survival signalling through mitochondrial proteins mitofusin and Bcl-xL. These mitochondrial proteins work towards maintaining mitochondrial bioenergetics and function and, in turn, enable CRC cell survival and tumour progression. Dashed lines represent avenues that have not been investigated. TCA, tricarboxylic acid cycle.

Fig. 4 |. Inflammatory bowel diseases and colorectal cancer therapeutics involving mitochondria.

When considering the divergent roles of mitochondria in inflammatory bowel disease (IBD) versus colorectal cancer (CRC), mitochondrial-targeted therapeutics result in distinct outcomes for these diseases. In IBD, mitochondria are crucial for the intestinal stem cell (ISC) niche and intestinal epithelial cell (IEC) function, impinging on the restoration of the epithelial barrier and wound healing, and therefore, therapeutics are tasked with enhancing mitochondrial function and dampening pathological reactive oxygen species (ROS). By contrast, CRC therapeutics involving mitochondria act to dampen mitochondrial function and induce tumour cell death. a, IBD therapeutics include mitochondrial ROS (mtROS) inhibitors, such as mitoquinone (MitoQ), or inhibitors of NLRP3-related pathways (such as GSK1070806, fenofibrate and atorvastatin) to dampen pathological outcomes. Activators of mitochondrial biogenesis (rosiglitazone and nicotinamide riboside) aim to restore and/or enhance the mitochondrial pool. Metformin exhibits multiple mechanisms of efficacy that can include electron transport chain complex I inhibition that might induce beneficial mtROS signalling. Long-standing ulcerative colitis therapy 5-ASA efficacy involves antioxidant and PPARγ agonist properties, suggesting that 5-aminosalicylic acid (5-ASA) might be beneficial in protecting from mitochondrial damage via ROS inhibition and activation of PGC1A-mitochondrial biogenesis. b, In CRC, mitochondria-targeted drugs can be categorized as inhibitors of mitochondrial respiration (metformin, mito-CP, 5-ASA, devimistat and penicillin), ROS agonists that cause damage to the mitochondrial structure, resulting in loss of mitochondrial function, inhibition of CRC proliferation and migration and induction of cell death (devimistat and cirsiliol) and inducers of caspase-mediated death that cause release of the apoptotic protein cytochrome c from the mitochondria and trigger apoptotic death of CRC cells (5-ASA, aspirin and penicillin). mito-CP, mitochondria-targeted carboxy proxyl; NLRP3, nucleotide-binding domain and leucine-rich repeat pyrin 3 domain.