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Review
. 2020 Sep 5:6:80.
doi: 10.1038/s41420-020-00316-9. eCollection 2020.

Mitochondrial dysfunction in fibrotic diseases

Affiliations
Review

Mitochondrial dysfunction in fibrotic diseases

Xinyu Li et al. Cell Death Discov. .

Abstract

Although fibrosis is a common pathological feature of most end-stage organ diseases, its pathogenesis remains unclear. There is growing evidence that mitochondrial dysfunction contributes to the development and progression of fibrosis. The heart, liver, kidney and lung are highly oxygen-consuming organs that are sensitive to mitochondrial dysfunction. Moreover, the fibrotic process of skin and islet is closely related to mitochondrial dysfunction as well. This review summarized emerging mechanisms related to mitochondrial dysfunction in different fibrotic organs and tissues above. First, it highlighted the important elucidation of mitochondria morphological changes, mitochondrial membrane potential and structural damage, mitochondrial DNA (mtDNA) damage and reactive oxidative species (ROS) production, etc. Second, it introduced the abnormality of mitophagy and mitochondrial transfer also contributed to the fibrotic process. Therefore, with gaining the increasing knowledge of mitochondrial structure, function, and origin, we could kindle a new era for the diagnostic and therapeutic strategies of many fibrotic diseases based on mitochondrial dysfunction.

Keywords: Metabolic disorders; Mitochondria.

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Conflict of interest statement

Conflict of interestThe authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Mitochondrial dysfunction in cardiac fibrosis.
Cardiac fibrosis, heart injury, and mitochondrial dysfunction are mutually causal, and the mechanisms overlap. Mitochondrial dysfunction is accompanied by morphological changes, mitochondrial membrane potential, and structural damage, and mtROS production. Excessive mtROS will destroy the normal structure and function of mitochondria, which further leads to the disorder of mitochondrial metabolic function. The release of risk factors like ROS and CytC from mitochondria further aggravates injury and inflammation. Meanwhile, transcriptional regulator deficiency and inhibited mitochondrial biogenesis pathways limit the self-repair function. NLRP3 which was localized to mitochondria regulates myofibroblast differentiation and Smad signal transduction by inducing ROS. As one of the protective pathways, UCP3 and NO/sGC can reduce ROS by mild decoupling and upregulating MnSOD.
Fig. 2
Fig. 2. Mitochondrial dysfunction in pulmonary fibrosis.
The mitochondrial dysfunction of different cells shows different characteristics in pulmonary fibrosis. The mitochondrial abnormalities and mitochondria-mediated apoptosis in AECs could conduce to pulmonary fibrosis in a critical way. HIF, high level of mtROS and endogenous TGF-β1 signaling interact with apoptosis and EMT. In AMs, Akt1-mediated mtROS could cause mitophagy, which contributed to the apoptotic resistance of pro-fibrotic AMs. As a risk factor in fibrosis, TGF-β1 was activated in response to ROS and NLRP3 inflammasome, which could also induce mitochondrial dysfunction in AMs. The deficiency of NOX4 reduced the mitochondrial fatty acid oxidation, which could inhibit NLRP3 inflammasome activation. ROS produced by complex III were required for TGF-β to induce gene expression in human lung fibroblasts. In turn, TGF-β could also increase the ROS level through the mechanism like inhibition of complex IV. Moreover, generation of H2O2 dependent on NOX4 was demanded for myofibroblast differentiation induced by TGF-β. Furthermore, the metabolic reprogramming in myofibroblast shows a augmented glycolysis, which contributed to pulmonary fibrosis via promoting the stabilization of HIF-1α.
Fig. 3
Fig. 3. Mitochondrial dysfunction in hepatic fibrosis.
The proliferation and activation of HSCs is the central process during the development of HF. Inhibition of ALR expression aggravates liver fibrosis, probably via promoting HSC migration and mitochondrial fusion. The increased mitochondrial Ca2+ influx induced by ALR in HSCs attributes the HSC migration. The activation of PARP can aggravate hepatic fibrosis via deteriorating the abnormal ETC including the inhibition of complexes I and IV. p66Shc can contribute to hepatic fibrosis through the activation of HSCs via upregulating mtROS production and NLRP3 expression. Didymin can improve the hepatic fibrosis main by inhibition of ERK/MAPK and PI3K/Akt pathways via up-regulation of RKIP expression in HSCs. The NLRP3 inflammasome activated by NOX4-independent ROS can mediate activation of HSCs via inducing pro-inflammatory factor including IL-1β.
Fig. 4
Fig. 4. Mitochondrial dysfunction in islet fibrosis.
Activated PSCs play a critical role in the remodeling of peripheral ECM, which mediates apoptosis and islet fibrosis by inducing mitochondrial dysfunction of islet cells. Selectively inducing PSCs apoptosis via mitochondrial pathway is a feasible strategy. Furthermore, activated PSCs mainly relies on oxidative phosphorylation of mitochondria to maintain ATP energy levels. The uncoupling of mitochondria decreases oxidative phosphorylation and ATP level to inhibit PSCs activation. But this low cell energy situation can promote the phenotype transformation of AAMs through IL-4 secretion.

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References

    1. Humphreys BD. Mechanisms of renal fibrosis. Annu. Rev. Physiol. 2018;80:309–326. - PubMed
    1. Ge PS, Runyon BA. Treatment of patients with cirrhosis. N. Engl. J. Med. 2016;375:767–777. - PubMed
    1. Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J. Cachexia Sarcopenia Muscle. 2017;8:349–369. - PMC - PubMed
    1. Topf U, Wrobel L, Chacinska A. Chatty mitochondria: keeping balance in cellular protein homeostasis. Trends Cell Biol. 2016;26:577–586. - PubMed
    1. Moon, et al. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat. Med. 2016;22:1002–1012. - PMC - PubMed