The role of RIPK3 in liver mitochondria bioenergetics and function

Abstract

Mitochondria are key players in cellular energy homeostasis. Staying at the centre of cellular metabolism, mitochondria serve a pivotal role in ATP generation via oxidative phosphorylation (OXPHOS). They have also been implicated in the regulation of various types of cell death, with specific molecular mechanisms, generally termed as regulated cell death. 1,2 Because mitochondria are essential for energy homeostasis, they must withstand dangerous external and internal stressors, including microbial infection, drugs, xenobiotics and metabolic dysregulation. 1,3 Impaired mitochondrial function, therefore, leads to abnormal production of reactive oxygen species (ROS), defective mitochondrial respiratory chain (MRC) activity or calcium overload, which eventually precedes cellular death. 1,4,5 Necroptosis is the most well-understood regulated necrosis form as it is closely associated with the same upstream signalling molecules as apoptosis. 2,6 In turn, passive necrosis that is triggered primarily by microbial infection and physiochemical stressors (e.g. radiation) shares morphological features with necroptosis, including rapid cytoplasmic and organelle (e.g. mitochondria) swelling, plasma membrane permeabilization and subsequent leakage of damage-associated

Mediators of necroptosis: from cell death to metabolic regulation

“…Moreover, Rip3 deficiency influences the hepatic lipidome in the context of choline-deficient amino acid (CDAA) diet-induced steatohepatitis through the up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) (Afonso et al, 2021 ). Functional studies in mice and hepatocytes provide insights into the role of RIP3 in mitochondrial and lipid droplet (LD) biology (Afonso et al, 2023 ; Islam et al, 2022 ). RIP3 interacts with key mitochondrial constituents, such as voltage-dependent anion channel (VDAC), mitochondrial antiviral-signaling protein (MAVS), mitochondrial permeability transition pore (mPTP), and metabolic enzymes including pyruvate dehydrogenase (PDH), glycogen phosphorylase (PYGL), glutamate-ammonia ligase (GLUL), and glutamate dehydrogenase 1 (GLUD1) (Islam et al, 2022 ; Qiu et al, 2018 ; Yang et al, 2018 ).…”

“…Functional studies in mice and hepatocytes provide insights into the role of RIP3 in mitochondrial and lipid droplet (LD) biology (Afonso et al, 2023 ; Islam et al, 2022 ). RIP3 interacts with key mitochondrial constituents, such as voltage-dependent anion channel (VDAC), mitochondrial antiviral-signaling protein (MAVS), mitochondrial permeability transition pore (mPTP), and metabolic enzymes including pyruvate dehydrogenase (PDH), glycogen phosphorylase (PYGL), glutamate-ammonia ligase (GLUL), and glutamate dehydrogenase 1 (GLUD1) (Islam et al, 2022 ; Qiu et al, 2018 ; Yang et al, 2018 ). These interactions play a role in modulating mitochondrial function and lipid metabolism.…”

Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis

“…5E to H). In addition, the expression of NLRP3 in ammasome and the regulator of liver in ammatory necroptosis RIPK3 [18,19] were also signi cantly increased in the knockout group (Fig. 5I and J).…”

Cell death and inflammation during obesity: “Know my methods, WAT(son)”

“…It is thus, intriguing, to speculate that, in adipocytes, RIPK3 serves as an inflammatory modulator rather than a killer protein. Notably, RIPK3 was reported to have a role in mitochondrial biogenesis and fatty acid oxidation in tumour associated macrophages [ 75 – 77 ]. Hence, RIPK3 may play a role in obesity-induced inflammation by mechanisms that go beyond necroptosis, possibly by preventing apoptosis in WAT or by direct regulation of inflammation and energy homeostasis (Table 2 ).…”