Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology

Abstract

Mitochondria are a class of dynamic organelles that constantly undergo fission and fusion. Mitochondrial dynamics is governed by a complex molecular machinery and finely tuned by regulatory proteins. During cell injury or stress, the dynamics is shifted to fission, resulting in mitochondrial fragmentation, which contributes to mitochondrial damage and consequent cell injury and death. Emerging evidence has suggested a role of mitochondrial fragmentation in the pathogenesis of renal diseases including acute kidney injury and diabetic nephropathy. A better understanding of the regulation of mitochondrial dynamics and its pathogenic changes may unveil novel therapeutic strategies.

Figure 1

(A) Diagram of mitochondrial fusion-fission. Mitochondria are dynamic organelles that constantly undergo fusion and fission processes to maintain an interconnected network in healthy cells. Mitochondrial fusion is mediated by Mfn1, Mfn2, and OPA1, while fission mainly involves Drp1 and Fis1. (B, C) Mitochondrial morphology in human kidney tubular epithelial (HK-2) cells. A control HK2 cell shows filamentous mitochondria (B), whereas mitochondria become fragmented in high glucose treated cells (C). Red: mitochondria; Blue: Nuclei.

Figure 2. Schematic diagrams of mitochondrial fission machinery

(A) Drp1 consists of an N-terminal GTPase, a central domain and a C-terminal GTPase effector domain (GED). Fis1 includes two central tandem tetratricopeptide repeats (TPRs) and a single C-terminal transmembrane (TM) domain, which facilitate Fis1 anchoring on the OMM. (B) Upon stimulation, Drp1 is activated and translocates to the scission sites of OMM through interaction with Fis1, where they oligomerize and form spirals to constrict OMM through GTP hydrolysis, resulting in mitochondrial fission.

Figure 3. Schematic diagrams of mitochondrial fusion machinery

(A) Mfn 1 and 2 contain an N-terminal GTPase domain, two transmembrane (TM) domains and two separating heptad repeat regions (HR1 and HR2). OPA1 comprises an N-terminal mitochondrial targeting sequence (MTS), GED at the C-terminus and other functional domains inbetween. (B) Mfn1 and 2 mediate OMM tethering through interaction of adjacent C-terminal HR2 regions, which leads to subsequent OMM fusion by GTP hydrolysis via Mfn. OPA1 is required in IMM fusion and the maintenance of cristae structure.

Figure 4. Mechanisms of mitochondrial fragmentation in cell death

Upon cellular stress, Drp1 is activated and translocates to mitochondria to initiate mitochondrial fission by form a spiral constriction ring. Meanwhile, Bak is activated resulting in a shift of binding to Mfn1 and arrest of mitochondrial fusion. Together, the activation of mitochondrial fission and the arrest of mitochondrial fusion result in mitochondrial fragmentation. Fragmented mitochondria are sensitized to Bax insertion and oligomerization to induce the formation of pathological pores, i.e. MOMP, to trigger cell death. Drp1 is regulated by multiple post-translational modifications that may be induced by the increases of intracellular Ca2+ and ROS. In addition, Ca2+ and ROS can trigger MPT to induce MOMP or, directly, necrosis. As a cytoprotective mechanism, autophagy may remove fragmented mitochondria via mitophagy to suppress cell death.

Figure 5. Hypothetic model for Bax/Bak regulation of mitochondrial dynamics during apoptosis

In unstressed cells, Bak interacts with both Mfn1 and 2 to maintain a filamentous mitochondrial network, while Bax is in an inactive form in the cytosol. Following apoptotic stress, Bak dissociates from Mfn2 and increases its association with Mfn1, resulting in the suppression of mitochondrial fusion and mitochondrial fragmentation (Hit 1). Meanwhile, Bax is activated and translocates to mitochondria. Fragmented mitochondria are sensitized to Bax insertion and oligomerization (Hit 2), leading to the formation of pathological pores for the release of apoptogenic factors such as cytochrome c.

Figure 6. Mitochondrial fragmentation in AKI

(A) A cultured renal tubular cell under control conditions shows a filamentous morphology of mitochondria, which become fragmented upon ATP-depletion. (B) Images of electron microscopy showing elongated mitochondria in a proximal tubular cell in kidney tissues and fragmented mitochondria in ischemically injured tubular cells. The images are adopted from Brooks et al. J Clin Invest. 119:1275–85, 2009.