FIS1

The protein encoded by this gene is a 16 kDa integral protein situated in the outer mitochondrial membrane (OMM).[9] It is composed of a transmembrane domain at the C-terminal and a cytosolic domain at the N-terminal.[9][13][14] The transmembrane domain anchors FIS1 in the OMM, though it has been observed to target different cellular compartments, such as the peroxisome, depending on its hydrophobicity, charge, and length.[14][15] Meanwhile, the cytosolic domain contains a bundle of six helices, four of which contain two tandem tetratricopeptide repeat (TPR)-like motifs. These motifs form a concave surface by their combined superhelical structure and potentially bind another FIS1 protein to form a dimer, or other proteins.[9][13] Moreover, the N-terminal arm can dock at, and thus obstruct, the TPR motifs, allowing the protein to exist in a dynamic equilibrium between “open” and “closed” states.[13]

FIS1 is indirectly involved in mitochondrial fission via binding dynamin-related protein 1 (DRP1).[12][15] By extension, FIS1 helps regulate the size and distribution of mitochondria in response to local demand for ATP or calcium ions.[13] In addition, mitochondrial fission may lead to release of cytochrome C, which eventually leads to cell death.[9] In a separate apoptotic signalling pathway, FIS1 interacts with BCAP31 to form a complex, the ARCosome. The ARCosome promotes cell death by bridging the mitochondria and the endoplasmic reticulum (ER), allowing FIS1 to transmit a proapoptotic signal from the mitochondria to the ER and activate procaspase-8. The ARCosome then forms a platform with procaspase-8 to increase calcium load in the mitochondria, resulting in apoptosis.[8][12] Additionally, FIS1 is involved in other modes of shaping mitochondrial morphology. For example, it interacts with TBC1D15 to regulate mitochondrial morphology, particularly with regard to lysosome and endosome fusion.[14] FIS1 also prevents mitochondria elongation, which would otherwise lead to cell cycle delay or arrest, and ultimately, senescence. Moreover, mitochondrial dysfunction results in elevated reactive oxygen species (ROS) levels, which cause DNA damage and induce transcriptional repression, as well as induce mitophagy.[9][10]

As a fission factor, FIS1 is associated with neurodegenerative diseases.[11][12] Stress, such as NO, can trigger aberrant mitochondrial fission and fusion, resulting in mitophagy.[9][11] For example, increased mitochondrial fragmentation and FIS1 levels were observed in Alzheimer’s disease (AD) patients. Thus, FIS1 could serve as a biomarker for early detection of AD.[11] FIS1 is also implicated in a variety of cancers, including acute myeloid leukemia, breast cancer, and prostate cancer.[12]

FIS1 has been shown to interact with:

• BCAP31,[8]
• procaspase-8,[8]
• TBC1D15,[14]
• PEX11 family,[15] and
• DNM1L.[16]