From mitochondria to heart: the role and challenges of mitochondrial antiviral signaling protein in cardiovascular disease

Abstract

Mitochondrial Antiviral Signaling Protein (MAVS) is a pivotal adaptor protein in the innate immune response, mediating the activation of NF-κB and type I interferon signaling pathways during viral infections. As an integral component of the mitochondrial outer membrane, MAVS also plays critical roles in the regulation of apoptosis, cellular metabolism, and the activation of inflammasomes, including NLRP3 and caspase family members. Emerging evidence indicates that MAVS is not only essential in antiviral defense but also contributes significantly to the pathogenesis of various diseases, notably cardiovascular diseases. In this review, we provide a comprehensive overview of the molecular structure of MAVS and the regulatory mechanisms modulating its activity. We further highlight the involvement of MAVS in the development of cardiovascular diseases through its participation in innate immune signaling and mitochondrial dynamics. Particular attention is given to the regulation of MAVS by post-translational modifications-such as ubiquitination, methylation, and acetylation-as well as by microRNAs and other mitochondria-associated proteins. These insights aim to deepen the understanding of MAVS as a potential biomarker and therapeutic target, offering novel perspectives for the prevention, diagnosis, and immunotherapeutic intervention of cardiovascular diseases.

Keywords: cardiovascular diseases; inflammation; innate immunity; mitochondrial antiviral signaling protein (MAVS); mitochondrial homeostasis.

Figure 1

Represented illustration of the main domains of MAVS. CARD domain (green) of MAVS interacts with the CARD domains of RIG-I and MDA5, thereby initiating the antiviral signaling cascade; TIM (red) in the PRR domain interacts with TRAF family members, activating the IKK and TBK-1 complex. PRD (yellow) participates in recruiting E3 ubiquitin ligase; TM (purple) anchors MAVS to the outer membrane of mitochondria, ensuring its stability and effectiveness. Created with Biorender.com.

Figure 2

Represented illustration of MAVS antiviral signal simulation pathway. Interactions between CARD domains enable RIG-I and MDA5 activated by viruses to interact with MAVS. Upon PRR stimulation, MAVS triggers downstream signaling cascades by recruiting TRAF. MAVS activates two cytosolic protein kinase complexes, leading to the production of immune factors. The TBK1 complex phosphorylates IRF-3/7, promoting the transcription of IFN genes. Simultaneously, the IKK complex activates NF-kB, resulting in the production of proinflammatory cytokines. NLRP3 binds to MAVS to promote the production of IL-1β through its PYD in PRR. CARD, caspase activation and recruitment domain; PRR, proline-rich region; TM, transmembrane domain; RIG-Ⅰ, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated gene 5; NLRP3, NOD-like receptor protein 3; TRAF, tumor necrosis factor receptor associated factor. Created with Biorender.com.

Figure 3

Main mechanisms of MAVS in cardiovascular diseases. The role of MAVS in viral myocarditis, MIRI, acute myocardial infarction, and HF. The knock down of MAVS or abnormal activation causes different pathological changes such as lipid metabolism disturbing, inflammation and mitochondrial damage, leading to cardiac dysfunction and aggravating HF. When viruses are infected, RIG-I and MDA5 interact with MAVS and activate the antiviral signal pathway; the expression of TRIM21 is upgraded and can cause k27-linked polyubiquitination of MAVS; ADAM9 leads to MAVS oligomerization. In AMI, TAX1BP1 interacts with RNF34, interrupting the autophagic degradation of MAVS, and inhibits the interacting between MAVS and NLRP3, leading to mitochondrial damage and exacerbate cardiac dysfunction. Created with Biorender.com.