ARF in the mitochondria: The last frontier?

Amino terminal hydrophobic import signals target the p14ARF tumor suppressor to the mitochondria

“…21 In particular, we confirm serine protease that cannot penetrate mitochondrial membranes. Truncated forms of p14 ARF that co-localized with mitochondria, including the melanoma-associated carboxy-terminal truncation (p14 ; Fig.…”

“…25 It is not possible to quantify mitochondrial localisation as an unknown proportion of cells remain unlysed in all mitochondrial fractionation protocols and the efficiency of protein recovery from each fraction may vary. 15,21 Interestingly, our data matched computer predictions of the likelihood of mitochondrial targeting. Analysis of p14 ARF1-64 and p14 ARF65-132 using the MitoProt TM algorithm resulted in an 86% and 7% predicted probability of mitochondrial import.…”

“…Certainly, sequences other than the p32-binding domain are required for mobilisation of p14 ARF into the mitochondria, as the C-terminal half of p14 ARF , which effectively binds p32, fails to accumulate in mitochondria. 21 In this report we re-analysed the localisation of human p14 ARF in order to define import sequences required for mitochondrial targeting. We now report that the p32 binding sequence is not essential for the mitochondrial accumulation of p14 ARF .…”

“…Initial results showing mitochondria localisation of ectopically expressed h-smARF 18 were not reproduced in a later study analysing endogenous h-smARF in cancer cells. 21 It has been suggested that full-length human and murine ARF are also recruited to mitochondria; significant but minor amounts (less than 5%) of endogenous p14 ARF and p19 ARF were detected in mitochondrial preparations derived from human tumor cells and mouse embryonic fibroblasts (MEFs). 21,22 Full-length p19 ARF and p14 ARF are also capable of binding p32, 16,18 and the mitochondrial localisation of p14 ARF required interaction with p32 via the p14 ARF tumor suppressor is frequently targeted for inactivation in many human cancers and in individuals predisposed to cutaneous melanoma.…”

A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility

“…In various cellular model systems, ARF interacts with p32 and induces mitochondrial membrane depolarization, leading to apoptotic or autophagic cell death responses 38,54 . Small fractions of endogenous ARF have been demonstrated in mitochondrial preparations from MEFs and human tumour cells 55 ; however, the functional significance of endogenous mitochondrial ARF has not been determined, partly because cellular signals or mechanisms that could trigger translocation of ARF to mitochondria have remained elusive. Our investigation of ARF in the melanocytic lineage was prompted by previous work 14,19,52 .…”