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Mitochondrial transcription factor a (TFAM): a novel brain intercellular signaling molecule and microglial activator

Microglia are a subtype of the non-neuronal glial cells that participate in the immune responses of the central nervous system (CNS). Evidence suggests that microglial activation contributes to neuronal death in neurodegenerative diseases. Microglia can be activated by a variety of exogenous stimuli, including toxins or infectious agents, as well as by endogenous pathology-associated molecules such as α-synuclein in Parkinson’s disease or amyloid-β protein in Alzheimer’s disease. Studies suggest that some endogenous molecules, which do not have a pathological origin, can also activate microglia. Damage associated molecular patterns (DAMPs) are an example of such endogenous molecules. When released from damaged or dying cells, DAMPs can trigger microglial activation through specific receptors, generating an inflammatory response. Mitochondrial transcription factor A (TFAM) has recently been implicated as a possible DAMP that is detected by peripheral immune cells. However, the effects of extracellular TFAM on CNS glial and neuronal cells have not been explored. Our study implicates TFAM as an activator of human peripheral blood monocytes, human THP-1 monocytic cells and human primary microglia isolated from adult brain tissues. Interaction of TFAM with these cell types leads to induction of pro-inflammatory cytokines and cytotoxic secretions, which may contribute to neuronal death. In this brief review, we describe endogenous signaling molecules capable of microglial activation with a specific focus on the potential involvement of TFAM. Elucidating the role of endogenous intercellular signaling molecules, such as TFAM, in CNS cell communication could expand the fundamental knowledge of glial-neuronal cell interactions and provide new insights into the mechanisms underlying glial cell activation. Such studies could facilitate the identification of novel therapeutic targets for a variety of pathologies that involve sterile neuroinflammatory processes.