Neuronal mitochondria dysfunction and neuroinflammation are two prominent pathological features increasingly realized as important pathogenic mechanisms for neurodegenerative diseases. However, little attempt has been taken to investigate the likely interactions between them. Mitofusin2 (Mfn2) is a mitochondrial outer membrane protein regulating mitochondrial fusion, a dynamic process essential for mitochondrial function. To explore the significance of neuronal mitochondria in the regulation of neuroinflammation, male and female transgenic mice with forced overexpression of Mfn2 specifically in neurons were intraperitoneally injected with lipopolysaccharide (LPS), a widely used approach to model neurodegeneration-associated neuroinflammation. Remarkably, LPS-induced lethality was almost completely abrogated in neuronal Mfn2 overexpression mice. Compared with nontransgenic wild-type mice, mice with neuronal Mfn2 overexpression also exhibited alleviated bodyweight loss, behavioral sickness, and myocardial dysfunction. LPS-induced release of IL-1␤ but not TNF-␣ was further found greatly inhibited in the CNS of mice with neuronal Mfn2 overexpression, whereas peripheral inflammatory responses in the blood, heart, lung, and spleen remained unchanged. At the cellular and molecular levels, neuronal Mfn2 suppressed the activation of microglia, prevented LPS-induced mitochondrial fragmentation in neurons, and importantly, upregulated the expression of CX3CL1, a unique chemokine constitutively produced by neurons to suppress microglial activation. Together, these results reveal an unrecognized possible role of neuronal mitochondria in the regulation of microglial activation, and propose neuronal Mfn2 as a likely mechanistic linker between neuronal mitochondria dysfunction and neuroinflammation in neurodegeneration.

Skeletal muscles undergo atrophy in response to diseases and aging. Here we report that mitofusin 2 (Mfn2) acts as a dominant suppressor of neuromuscular synaptic loss to preserve skeletal muscles. Mfn2 is reduced in spinal cords of transgenic SOD1 and aged mice. Through preserving neuromuscular synapses, increasing neuronal Mfn2 prevents skeletal muscle wasting in both SOD1 and aged mice, whereas deletion of neuronal Mfn2 produces neuromuscular synaptic dysfunction and skeletal muscle atrophy. Neuromuscular synaptic loss after sciatic nerve transection can also be alleviated by Mfn2. Mfn2 coexists with calpastatin largely in mitochondria-associated membranes (MAMs) to regulate its axonal transport. Genetic inactivation of calpastatin abolishes Mfn2-mediated protection of neuromuscular synapses. Our results suggest that, as a potential key component of a novel and heretofore unrecognized mechanism of cytoplasmic protein transport, Mfn2 may play a general role in preserving neuromuscular synapses and serve as a common therapeutic target for skeletal muscle atrophy.

The involvement of complement in B2 cell responses has been regarded as occurring strictly via complement components in plasma. In this study, we show that Ab production and class switch recombination (CSR) depend on autocrine C3a and C5a receptor (C3ar1/ C5ar1) signaling in B2 cells. CD40 upregulation, IL-6 production, growth in response to BAFF or APRIL, and AID/Bcl-6 expression, as well as follicular CD4 + cell CD21 production, all depended on this signal transduction. OVA immunization of C3ar1 2/2 C5ar1 2/2 mice elicited IgM Ab but no other isotypes, whereas decay accelerating factor (Daf1) 2/2 mice elicited more robust Ab production and CSR than wild-type (WT) mice. Comparable differences occurred in OVA-immunized mMT recipients of WT, C3ar1 2/2 C5ar1 2/2 , and Daf1 2/2 B2 cells and in hen egg lysozyme-immunized mMT recipients of MD4 B2 cells on each genetic background. B2 cells produced factor I and C3 and autophosphorylated CD19. Immunized C3 2/2 C5 2/2 recipients of WT MD4 bone marrow efficiently produced Ab. Thus, B2 cellproduced complement participates in B2 cell activation.