The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

Abstract

Mitochondria are dynamic organelles that alter their organization in response to a variety of cellular cues. Mitochondria are central in many biologic processes, such as cellular bioenergetics and apoptosis, and mitochondrial network morphology can contribute to those physiologic processes. Some of the biologic processes that are in part governed by mitochondria are also commonly deregulated in cancers. Furthermore, patient tumor samples from a variety of cancers have revealed that mitochondrial dynamics machinery may be deregulated in tumors. In this review, we will discuss how commonly mutated oncogenes and their downstream effector pathways regulate the mitochondrial dynamics machinery to promote changes in mitochondrial morphology as well as the physiologic consequences of altered mitochondrial morphology for tumorigenic growth.

Keywords: cancer; mitochondrial dynamics; oncogenic signaling.

Figure 1

The primary mitochondrial dynamics machinery responsible for mitochondrial membrane fusion and fission. Outer mitochondrial membrane fusion is primarily mediated by mitofusin 1 and 2 (Mfn1 and Mfn2). (A–C) Homotypic Mfn1 and Mfn2 complexes or heterotypic Mfn1:Mfn2 complexes execute outer membrane fusion. (D) Optic atrophy 1 (Opa1) is the large guanosine triphosphate hydrolase (GTPase) that mediates inner mitochondrial membrane fusion. Inner mitochondrial membrane fusion is typically coupled with outer mitochondrial membrane fusion. (E) Dynamin-related protein 1 (Drp1) oligomerizes as spirals around the mitochondrial membrane. Upon GTP hydrolysis, the mitochondria are greatly constricted which serves as the platform for Dynamin-2 (Dyn2) to complete fission of the mitochondrial unit.

Figure 2

The reciprocal regulation of the mitochondrial dynamics machinery by the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways. The activated MAPK pathway promotes mitochondrial fission by activating Drp1 as well as inhibiting Mfn1 activity. Conversely, Mfn1 has been shown to interact with Ras while Mfn2 has been shown to interact with either Ras or Raf; these interactions have been shown to inhibit MAPK activity and some of its physiological consequences. Activated Akt can directly phosphorylate and activate Drp1 and promote mitochondrial fission. Additionally, Mfn2 can interact with the mammalian target of rapamycin complex 2 (mTORC2) complex, via interactions with rapamycin-insensitive companion of mTOR (RICTOR), which inhibits PI3K/Akt activity.

Figure 3

Oncogenic signals regulate the mitochondrial dynamics machinery to drive changes in mitochondrial morphology. Oncogenic MAPK, PI3K/Akt, and Ras-like guanine nucleotide exchange factor (RalGEF) signals promote mitochondrial fragmentation downstream of oncogenic Ras. Myc activity and canonical Wnt signaling, on the other hand, promote mitochondrial fusion, while non-canonical Wnt signaling and hypoxia induce fragmentation.