Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease

Abstract

Mitochondrial fission protein 1 (Fis1) was identified in yeast as being essential for mitochondrial division or fission and subsequently determined to mediate human mitochondrial and peroxisomal fission. Yet, its exact functions in humans, especially in regard to mitochondrial fission, remains an enigma as genetic deletion of Fis1 elongates mitochondria in some cell types, but not others. Fis1 has also been identified as an important component of apoptotic and mitophagic pathways suggesting the protein may have multiple, essential roles. This review presents current perspectives on the emerging functions of Fis1 and their implications in human health and diseases, with an emphasis on Fis1's role in both endocrine and neurological disorders.

Keywords: FIS1; apoptosis; cancer; diabetes; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases.

Figure 1

The structure of human Fis1. The structure of human Fis1 (NMR structure PDB: 1PC2). Fis1 is anchored to the mitochondrial outer membrane by a C-terminal transmembrane domain exposing a soluble domain to the cytoplasm that is comprised of two core tetratricopeptide repeat (TPR) structural motifs flanked by two helices (helices 1 and 6). The N-terminal region of Fis1 is referred to as the “N-terminal arm”. The transmembrane domain (TMD) has been truncated here and its structure in the membrane is unknown but presumably helical.

Figure 2

Functional evolution of Fis1 from yeast to humans. Fis1 interacting partners appear to differ between fungi and higher eukaryotes. In budding yeast, the fission mechanoenzyme Dnm1p is recruited to mitochondria by resident mitochondrial protein Fis1p with Mdv1p acting as an adapter. In yeast, Fis1p appears to play an early and late role in Dnm1p assembly (86). No human ortholog of Mdv1p has been identified to date, and human Fis1 is thought to recruit proteins other than the fission mechanoenzyme Drp1 to the mitochondrion (see text). The extent of the Fis1 interactome is not fully defined.

Figure 3

The proposed roles of human Fis1. Fis1 is proposed to participate in mitochondrial dynamics by stimulating mitochondrial fission via interactions with the mechanoenzyme Drp1, or by prevention of mitochondrial fusion through the inhibition of Mfn2/Opa1. Fis1 participates in mitophagy through recruitment of TBC1D15/17 and Syntaxin17 to mitochondria. Fis1 is also proposed to interact with BAP31, inciting apoptosis. Mitochondrial motility may occur through Fis1-induced mitochondrial clumping, or through interactions with the mitochondrial motility machinery consisting of TRAK, MIRO, and Kinesin. Fis1 has also been shown to participate in peroxisomal fission. It has also been suggested that Fis1 may be found at membrane contact sites, possibly in complex with BAP31 or Syntaxin17.

Figure 4

Fis1 expression in endocrine related diseases. Fis1 expression levels vary from abnormally low to high in different diseases, potentially impacting overall mitochondrial and cellular function.

Figure 5

Increased Fis1 expression is noted in numerous neurological disorders, resulting in impaired cellular function. Mitochondrial fragmentation is worsened by loss of C9ORF72, DJ-1, the presence of amyloid-beta, or MPTP. The compounds p110, SS-31, and resveratrol have been noted to decrease mitochondrial fragmentation in the setting of Fis1 upregulation in models of neurological disease.