AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes

Abstract

Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF ) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid β-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid β-oxidation (e.g., palmitic acid assimilation), the AIF thymocytes retrieved the ATP levels of the AIF cells. As a consequence, it was possible to significantly reestablish AIF thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIF-mediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.

Qishen granules exerts cardioprotective effects on rats with heart failure via regulating fatty acid and glucose metabolism

“…Furthermore, CPT1, which facilitates the transportation of long chain FA into the mitochondrial matrix [34], was also increased by treatment of QSG. ACADL, ACADM, ACAA2 and SCP2, the critical enzymes for β-oxidation of FA within the mitochondria [26][27][28]35], were all upregulated by QSG treatment, indicating that QSG could promote fatty acid β-oxidation.…”

“…FAT/ CD36 medicates the entry of long-chain FA into cardiac cells [25], and CPT1 is the rate-limiting enzyme for transportation of FA from cytoplasm to mitochondria [9]. ACADL, ACADM, ACAA2 and SCP2 facilitate the metabolism of FA through β-oxidation in mitochondria [26][27][28]. The protein levels of cardiac FAT/CD36, CPT1A, ACADL, ACADM, ACAA2 and SCP2 were all impressively reduced in the model group compared to the sham group (P < 0.05 or P < 0.01, Fig.…”

Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer

“…In this regard, downregulation of AIF or its binding partners (i.e., CypA, MIF) involved in chromatinolysis significantly reduces the brain damage following ischemic insults ( Zhu et al, 2007a ; Zhu et al, 2007b ; Culmsee et al, 2005 ; Wang et al, 2016b ; Wang et al, 2011 ). Apart from this evident neuron-specific role, one emerging aspect is the contribution of AIF to hematopoietic development and immune response, primarily through its role in mitochondrial bioenergetics ( Burguillos et al, 2011 ; Milasta et al, 2016 ; Cabon et al, 2018 ). In this context, it is tempting to speculate that AIF dysfunction may influence neurodegenerative processes in a non-cell-autonomous manner, by altering for example glia metabolism and inflammation.…”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…From a pharmacological perspective, several drugs could be used to activate Mfn1 and thus reverse mitochondrial function in the setting of cerebral IRI. These include melatonin and liraglutide . Resveratrol (3,5,4′‐trihydroxy‐trans‐stilbene) belongs to a class of compounds called plant polyphenols and is also a phytoalexin produced by plants during environmental stress and infections to help overcome their adverse effects .…”

“…These include melatonin and liraglutide. 25,26 Resveratrol (3,5,4′-trihydroxy-trans-stilbene) belongs to a class of compounds called plant polyphenols and is also a phytoalexin produced by plants during environmental stress and infections to help overcome their adverse effects. 27,28 This inherent ability to provide protection against stress conditions is the main feature that makes resveratrol an attractive candidate for prevention and treatment of human diseases.…”